利用疟原虫全基因组数据和分子对接方法预测青蒿素的抗疟靶点
|
摘要
人类同疟疾的斗争已有相当长的历史,但疟疾目前仍然是世界上分布和流行最广泛的寄生虫疾病之一。疟原虫耐药性的出现使得许多传统的抗疟药物如奎宁、氯喹、甲氟喹等已失去有效性。从菊科植物黄花蒿(Artemisia annua L.)中提取的抗疟药物青蒿素(QHS),一度被世界卫生组织誉为“治疗疟疾的最大希望”。但青蒿素存在着半衰期短、口服利用率低及复燃率较高的缺点,设计和合成高效低毒的青蒿素类抗疟化合物是药学和化学研究工作者备受关注的课题。纵观近年来,青蒿素类抗疟新药的研发一直处于停滞状态,其根本原因是该类衍生物的抗疟靶点不明确。药物靶点的确认是发现和设计优良药物的基础,分子对接和生物信息学相关的理论方法可以用于靶点的发现,并且不乏成功的实例。因此,本文主要围绕寻找青蒿素抗疟靶点这一主题进行生物信息学研究,将有助于青蒿素类抗疟衍生物的设计。
论文第一部分综述了国内外的各种观点,讨论了青蒿素衍生物的抗疟机制。目前研究表明,青蒿素是多途径、多靶点的抗疟机制,而疟原虫体内的SERCA型钙离子调节酶(pfATP6)普遍被认为是青蒿素抗疟作用的靶点。对于半胱氨酸蛋白酶(Falcipain-2,FP2)、翻译控制肿瘤相关蛋白(TCTP)和组氨酸蛋白2(HRP2)则没有足够可靠的证据说明它们是青蒿素类衍生物的抗疟靶蛋白。
在论文第二部分中,我们利用同源模建、分子对接和定量构效关系等多种方法从理论上阐明FP2、TCTP和HRP2是否为青蒿素类衍生物的抗疟靶点。在进行对接研究之前,我们首先采用同源模建的方式对pfATP6和TCTP的三维结构进行预测,并对最终模型进行合理性评价,结果令人满意。随后,在比较半经验、从头算法和密度泛函等五种理论方法对青蒿素配体几何构型优化的基础上,选用了精度和速度兼备的B3LYP/6-31G~*方法作为对接前配体的优化方法。笔者还以青蒿素和已知的靶点pfATP6为研究体系,测试了对接算法的准确性。这为下一步深入的对接和定量构效关系研究奠定了方法学基础。用Autodock程序比较研究了青蒿素、半胱氨酸蛋白酶特异性E64和脱氧青蒿素与FP2的相互作用模型,发现青蒿素与E64的对接模式类似,与无活性的脱氧青蒿素则截然不同。这些结果初步提示FP2可能为青蒿素的抗疟靶点。采用四个系列34种有代表性的青蒿素衍生物进一步研究与FP2形成的复合物模型。对接结果显示,所有的配体分子都采用了比较相似的构象与FP2结合,且结合自由能与抗疟活性线性相关。在此基础上,建立结合自由能与小分子多种描述符之间的定量构效关系模型。QSAR模型提示,对青蒿素的取代基进行修饰使其支化度增加,可以提高抗疟活性。另外,与FP2形成的氢键越多,过氧键所带的电荷越负,越有利于抗疟活性的提高。分子量增大,反而会降低抗疟活性。所得的模型不仅稳定显著,而且具有很好的外部预测能力。以分子对接模型为指导,结合构效关系的结果,确定FP2为青蒿素及其衍生物的另一抗疟靶点。我们还探讨了青蒿素和FP2作用的活性中间体,初步推测仲碳自由基可能为QHS-FP2酶促反应的中间体。将青蒿素及其34种衍生物与TCTP进行对接,配体的结合模型不仅没有表现出规律性,而且距离TCTP的关键残基Cys14较远,不存在成键的可能性。鉴于此,推测TCTP不是该类衍生物的抗疟靶点。结论的正确性有待于进一步的论证。另一蛋白HRP2与所有的青蒿素衍生物对接则一致结合在同一空腔内。由于HRP2缺乏结构方面的活性位点信息,这部分研究尚不完善,仍有较大探索空间。但对接研究得到青蒿素抑制HRP2的理论抑制常数与实验值几乎逼近,这点可以说明对接方法的可信度和合理性。
由于恶性疟原虫的全基因组已经测序完成,故本文第三部分将青蒿素的靶点研究扩展到全基因组水平上,从同源蛋白和信号通路两方面充分挖掘已有的生物信息学资源,以期获得有价值的青蒿素抗疟靶点。同源蛋白搜索、生物信息学分析和同源模建综合运用,结果发现,青蒿素的理论抗疟靶点FP2存在着两个高度同源蛋白FP2B和FP3。它们不仅一级序列相似,而且结构域和三维结构都高度保守。比较分析三个同源半胱氨酸蛋白酶与青蒿素的作用模式,发现青蒿素均能结合在不同受体的活性口袋,且结合作用能相当。从全基因组水平来看,青蒿素难以选择性地抑制疟原虫体内同源的三种半胱氨酸蛋白酶。由此提示,今后的青蒿素类抗疟药物筛选和设计要从半胱氨酸蛋白酶家族的抑制作用考虑。信号通路是生物体对外界刺激做出反应的物质基础,我们最后以信号通路为背景,探索性地研究青蒿素可能的抗疟靶点和作用的信号通路。整理搜集了8种信号通路上关键的蛋白酶与青蒿素进行对接,初步判断嘌呤核苷磷酸化酶(pfPNP)、肽脱甲酰基化酶(pfPDF)和核糖-5-磷酸异构酶(pfRpiA)可能为青蒿素的抗疟靶点。青蒿素可能干预的信号通路有:嘌呤代谢、嘧啶代谢、蛋氨酸代谢、乙醛酸和二羧酸代谢及磷酸戊糖途径。
There has been a long history of struggle against malaria. However, malaria has stillbeen one of the most widely distributed and epidemic parasitic diseases in the world.The emergency of malarial parasite resistance has rendered many traditional drugssuch as quinine, chloroquine and mefloquine ineffective. Qinghaosu (QHS), extractedfrom sweet wormwood Artemisia annua L, has been named as the 'biggest hope foreradicating malaria' by WHO. As artemisinin has limitations in terms of short halflife, low oral bioavailability and high recurrence, general interest of chemist andpharmaceutist is concerntrated on design and synthesis to develop new QHS-typedrugs with improved efficacy and low toxicity. Development process of novelQHS-type antimalarial drugs has stagnated in recent years. The basic reason is unclearantimalarial target of this compound. Identification of targets is the basis for rationaldrug design. Molecular docking and bioinformatics related methods are useful toolsfor drug target discovery, which have many successful cases in the application.Therefore, our theoretical investigations have focused on searching for antimalarialtargets of QHS. On the one hand, this will help in designing new QHS analogues; onthe other hand, it will also promote innovative chemotherapy of malaria.
Chapter 1 reviewed all the viewpoints in this field and discussed the antimalarialaction mode of QHS. The results indicated multi-target mechanism of action in manyways. But SERCA-type calcium-dependent ATPase (pfATP6) is generally known as amolecular target for QHS. There were no equally reliable evidences that indentifycysteine proteinase (Falcipain-2, FP2), translationally controlled tumor protein (TCTP)and His-rich protein 2 (HRP2) as antimalarial targets.
In Chapter 2, we performed homology modeling, molecular docking and quantitative structure-activity relationship (QSAR) to elucidate whether FP2、TCTP and HRP2 were antimalarial targets for QHS derivatives. Before we started molecular docking study, homology modeling had been applied to predict three-dimenision structures of pfATP6 and TCTP. Quality evaluation has proved the rationality of models.Compared with five computational methods including semi-empirical, ab initio and density functional theory, the advanced density functional theory both in speed and accuracy was employed to calculate the geometry optimization of ligands prior to molecular docking in the thesis. Docking between QHS and its known target pfATP6 was carried out to test the reliability of docking method. This laid the foundation of methodology for the following docking and QSAR study. Binding mode of QHS, cysteine proteinase specific inhibitor E64 and deoxyartemisinin (DQHS) with FP2, respectively, was compared by means of Autodock package. The docking results showed that binding mode of QHS was similar to that of E64 and completely different from that of DQHS. The preliminary study indicated that FP2 was the possible antimalarial target for QHS. Further study was conducted to investigate the complex between four series of 34 typical QHS derivates with FP2. The docking results showed all the lignds bind to FP2 in similar conformation. Furthermore, the binding free energy exhibited a good linear correlation with antimalarial activity. On the basis of previous study, QSAR model was built between binding free energy and many descriptors. According toQSAR model, introducing substitution to increase the degree of branching may enhance antimalarial activity. Moreover, the more formation of hydrogen bonds with FP2, the better the antimalarial activity. The negative charge of peroxide bridge oxygen atoms will benefit for improving antimalarial activity. On the contrary, increasing molecular weight will decrease antimalarial activity. The obtained model is not only significant, but also has good ability of external prediction. Combined with the results of molecular docking and QSAR, we confirmed FP2 was other molecular target for QHS, in addition to pfATP6. Theoretical study on the mechanism of QHS reaction with FP2 suggested that secondary radical was the possible active species. No regularity of binding model was found when docking QHS and its 34 derivates with TCTP. The distance between endoperoxide atoms and key residue Cys14 was too far to form chemical bonds. From this point of view, we assumed that TCTP was not the target for QHS derivates. The verification of results needs to be further validated. All the QHS derivates bind to HRP2 in the same pocket. Because of limited knowledge of active sites of HRP2, the definite conclusion can not be reached. The research still needs to be improved. The theoretical inhibition constants between artemisinin and HRP2 obtained from docking studies are very close to the experimental data. This proved the credibility and reasonability of docking method.
Since the complete genome sequence of Plasmodium falciparum has been published, Chapter 3 enlarged the artemisinin target research into the entire genomics. In order to obtain valuable antimalarial target of QHS, we exploited available bioinformatics resources from the following two aspects: homologous proteins and signaling pathways. Combination of homologous proteins searching, bioinformatics analysis with homology modeling, two highly homologous proteins for FP2, theoretical antimalarial targets of QHS, were found. There are FP2B and FP3. These proteins are not only similar in the primary sequence, but also highly conserved in the structure domain and the three-dimension structure. Comparing the binding patterns between three homologous cysteine proteases with QHS, we found that QHS can bind to the active pockets of different receptors. And the binding energies are at same level. At whole genome level, it is hard for QHS to selectively inhibit the three homologous cysteine proteases of malarial parasite in vivo. This suggested that we should consider the inhibition of whole cysteine proteases family during screening and designing QHS-type artimalarials. In particular, Signal pathway is the physical basis of organisms responding to stimulation from environment. Based on signal pathway database, exploratory experiments have been conducted to search the possible antimalarial targets and related signal pathways of QHS. 8 critical proteases in signal pathway were collected to dock with QHS. We assumed that pfPNP, pfPDF, and pfRpiA maybe the possible antimalarial targets. Signal pathways that might be interfered by QHS are purine metabolism, pyrimidine metabolism, Glyoxylate and dicarboxylate metabolism, methionine metabolism and pentose phosphate pathway.
论文第一部分综述了国内外的各种观点,讨论了青蒿素衍生物的抗疟机制。目前研究表明,青蒿素是多途径、多靶点的抗疟机制,而疟原虫体内的SERCA型钙离子调节酶(pfATP6)普遍被认为是青蒿素抗疟作用的靶点。对于半胱氨酸蛋白酶(Falcipain-2,FP2)、翻译控制肿瘤相关蛋白(TCTP)和组氨酸蛋白2(HRP2)则没有足够可靠的证据说明它们是青蒿素类衍生物的抗疟靶蛋白。
在论文第二部分中,我们利用同源模建、分子对接和定量构效关系等多种方法从理论上阐明FP2、TCTP和HRP2是否为青蒿素类衍生物的抗疟靶点。在进行对接研究之前,我们首先采用同源模建的方式对pfATP6和TCTP的三维结构进行预测,并对最终模型进行合理性评价,结果令人满意。随后,在比较半经验、从头算法和密度泛函等五种理论方法对青蒿素配体几何构型优化的基础上,选用了精度和速度兼备的B3LYP/6-31G~*方法作为对接前配体的优化方法。笔者还以青蒿素和已知的靶点pfATP6为研究体系,测试了对接算法的准确性。这为下一步深入的对接和定量构效关系研究奠定了方法学基础。用Autodock程序比较研究了青蒿素、半胱氨酸蛋白酶特异性E64和脱氧青蒿素与FP2的相互作用模型,发现青蒿素与E64的对接模式类似,与无活性的脱氧青蒿素则截然不同。这些结果初步提示FP2可能为青蒿素的抗疟靶点。采用四个系列34种有代表性的青蒿素衍生物进一步研究与FP2形成的复合物模型。对接结果显示,所有的配体分子都采用了比较相似的构象与FP2结合,且结合自由能与抗疟活性线性相关。在此基础上,建立结合自由能与小分子多种描述符之间的定量构效关系模型。QSAR模型提示,对青蒿素的取代基进行修饰使其支化度增加,可以提高抗疟活性。另外,与FP2形成的氢键越多,过氧键所带的电荷越负,越有利于抗疟活性的提高。分子量增大,反而会降低抗疟活性。所得的模型不仅稳定显著,而且具有很好的外部预测能力。以分子对接模型为指导,结合构效关系的结果,确定FP2为青蒿素及其衍生物的另一抗疟靶点。我们还探讨了青蒿素和FP2作用的活性中间体,初步推测仲碳自由基可能为QHS-FP2酶促反应的中间体。将青蒿素及其34种衍生物与TCTP进行对接,配体的结合模型不仅没有表现出规律性,而且距离TCTP的关键残基Cys14较远,不存在成键的可能性。鉴于此,推测TCTP不是该类衍生物的抗疟靶点。结论的正确性有待于进一步的论证。另一蛋白HRP2与所有的青蒿素衍生物对接则一致结合在同一空腔内。由于HRP2缺乏结构方面的活性位点信息,这部分研究尚不完善,仍有较大探索空间。但对接研究得到青蒿素抑制HRP2的理论抑制常数与实验值几乎逼近,这点可以说明对接方法的可信度和合理性。
由于恶性疟原虫的全基因组已经测序完成,故本文第三部分将青蒿素的靶点研究扩展到全基因组水平上,从同源蛋白和信号通路两方面充分挖掘已有的生物信息学资源,以期获得有价值的青蒿素抗疟靶点。同源蛋白搜索、生物信息学分析和同源模建综合运用,结果发现,青蒿素的理论抗疟靶点FP2存在着两个高度同源蛋白FP2B和FP3。它们不仅一级序列相似,而且结构域和三维结构都高度保守。比较分析三个同源半胱氨酸蛋白酶与青蒿素的作用模式,发现青蒿素均能结合在不同受体的活性口袋,且结合作用能相当。从全基因组水平来看,青蒿素难以选择性地抑制疟原虫体内同源的三种半胱氨酸蛋白酶。由此提示,今后的青蒿素类抗疟药物筛选和设计要从半胱氨酸蛋白酶家族的抑制作用考虑。信号通路是生物体对外界刺激做出反应的物质基础,我们最后以信号通路为背景,探索性地研究青蒿素可能的抗疟靶点和作用的信号通路。整理搜集了8种信号通路上关键的蛋白酶与青蒿素进行对接,初步判断嘌呤核苷磷酸化酶(pfPNP)、肽脱甲酰基化酶(pfPDF)和核糖-5-磷酸异构酶(pfRpiA)可能为青蒿素的抗疟靶点。青蒿素可能干预的信号通路有:嘌呤代谢、嘧啶代谢、蛋氨酸代谢、乙醛酸和二羧酸代谢及磷酸戊糖途径。
There has been a long history of struggle against malaria. However, malaria has stillbeen one of the most widely distributed and epidemic parasitic diseases in the world.The emergency of malarial parasite resistance has rendered many traditional drugssuch as quinine, chloroquine and mefloquine ineffective. Qinghaosu (QHS), extractedfrom sweet wormwood Artemisia annua L, has been named as the 'biggest hope foreradicating malaria' by WHO. As artemisinin has limitations in terms of short halflife, low oral bioavailability and high recurrence, general interest of chemist andpharmaceutist is concerntrated on design and synthesis to develop new QHS-typedrugs with improved efficacy and low toxicity. Development process of novelQHS-type antimalarial drugs has stagnated in recent years. The basic reason is unclearantimalarial target of this compound. Identification of targets is the basis for rationaldrug design. Molecular docking and bioinformatics related methods are useful toolsfor drug target discovery, which have many successful cases in the application.Therefore, our theoretical investigations have focused on searching for antimalarialtargets of QHS. On the one hand, this will help in designing new QHS analogues; onthe other hand, it will also promote innovative chemotherapy of malaria.
Chapter 1 reviewed all the viewpoints in this field and discussed the antimalarialaction mode of QHS. The results indicated multi-target mechanism of action in manyways. But SERCA-type calcium-dependent ATPase (pfATP6) is generally known as amolecular target for QHS. There were no equally reliable evidences that indentifycysteine proteinase (Falcipain-2, FP2), translationally controlled tumor protein (TCTP)and His-rich protein 2 (HRP2) as antimalarial targets.
In Chapter 2, we performed homology modeling, molecular docking and quantitative structure-activity relationship (QSAR) to elucidate whether FP2、TCTP and HRP2 were antimalarial targets for QHS derivatives. Before we started molecular docking study, homology modeling had been applied to predict three-dimenision structures of pfATP6 and TCTP. Quality evaluation has proved the rationality of models.Compared with five computational methods including semi-empirical, ab initio and density functional theory, the advanced density functional theory both in speed and accuracy was employed to calculate the geometry optimization of ligands prior to molecular docking in the thesis. Docking between QHS and its known target pfATP6 was carried out to test the reliability of docking method. This laid the foundation of methodology for the following docking and QSAR study. Binding mode of QHS, cysteine proteinase specific inhibitor E64 and deoxyartemisinin (DQHS) with FP2, respectively, was compared by means of Autodock package. The docking results showed that binding mode of QHS was similar to that of E64 and completely different from that of DQHS. The preliminary study indicated that FP2 was the possible antimalarial target for QHS. Further study was conducted to investigate the complex between four series of 34 typical QHS derivates with FP2. The docking results showed all the lignds bind to FP2 in similar conformation. Furthermore, the binding free energy exhibited a good linear correlation with antimalarial activity. On the basis of previous study, QSAR model was built between binding free energy and many descriptors. According toQSAR model, introducing substitution to increase the degree of branching may enhance antimalarial activity. Moreover, the more formation of hydrogen bonds with FP2, the better the antimalarial activity. The negative charge of peroxide bridge oxygen atoms will benefit for improving antimalarial activity. On the contrary, increasing molecular weight will decrease antimalarial activity. The obtained model is not only significant, but also has good ability of external prediction. Combined with the results of molecular docking and QSAR, we confirmed FP2 was other molecular target for QHS, in addition to pfATP6. Theoretical study on the mechanism of QHS reaction with FP2 suggested that secondary radical was the possible active species. No regularity of binding model was found when docking QHS and its 34 derivates with TCTP. The distance between endoperoxide atoms and key residue Cys14 was too far to form chemical bonds. From this point of view, we assumed that TCTP was not the target for QHS derivates. The verification of results needs to be further validated. All the QHS derivates bind to HRP2 in the same pocket. Because of limited knowledge of active sites of HRP2, the definite conclusion can not be reached. The research still needs to be improved. The theoretical inhibition constants between artemisinin and HRP2 obtained from docking studies are very close to the experimental data. This proved the credibility and reasonability of docking method.
Since the complete genome sequence of Plasmodium falciparum has been published, Chapter 3 enlarged the artemisinin target research into the entire genomics. In order to obtain valuable antimalarial target of QHS, we exploited available bioinformatics resources from the following two aspects: homologous proteins and signaling pathways. Combination of homologous proteins searching, bioinformatics analysis with homology modeling, two highly homologous proteins for FP2, theoretical antimalarial targets of QHS, were found. There are FP2B and FP3. These proteins are not only similar in the primary sequence, but also highly conserved in the structure domain and the three-dimension structure. Comparing the binding patterns between three homologous cysteine proteases with QHS, we found that QHS can bind to the active pockets of different receptors. And the binding energies are at same level. At whole genome level, it is hard for QHS to selectively inhibit the three homologous cysteine proteases of malarial parasite in vivo. This suggested that we should consider the inhibition of whole cysteine proteases family during screening and designing QHS-type artimalarials. In particular, Signal pathway is the physical basis of organisms responding to stimulation from environment. Based on signal pathway database, exploratory experiments have been conducted to search the possible antimalarial targets and related signal pathways of QHS. 8 critical proteases in signal pathway were collected to dock with QHS. We assumed that pfPNP, pfPDF, and pfRpiA maybe the possible antimalarial targets. Signal pathways that might be interfered by QHS are purine metabolism, pyrimidine metabolism, Glyoxylate and dicarboxylate metabolism, methionine metabolism and pentose phosphate pathway.
引文
[1]克瑞斯汀·格曼.疟疾其实比艾滋病更危险[J].国外社会科学文摘,2006,1:44-46.
[2]WHO Healthe Organization.World Malaria Report 2008[M].2008:9.
[3]李华宪,陈国伟,杨沅川等.云南省2001-2005年疟疾疫情分析[J].中国寄生虫学与寄生虫病杂志,2008,26(1):46-49.
[4]卫疾控发(2006)70号.2006-2015年全国疟疾防治规划[J].中华人民共和国卫生部公报,2006,3:50-53.
[5]周水森,王漪,汤林华.2006年全国疟疾形势[J].中国寄生虫学与寄生虫病杂志,2007,25(6):439-441.
[6]Roger B.Rolling Back Malaria:Rhetoric and Reality in the Fight against a Deadly Killer[EB].AEI,2008-4-24.
[7]Wemsdorfer WH.抗药性疟疾的流行病学[J].国外医学寄生虫病分册,1994,21(5):196-199.
[8]Liu JM,Ni MY,Fan JF,et al.The structure and reaction of Qinghaosu[J].Acta Chim Sinica,1979,37:129-141.
[9]China cooperative research group on Qinghaosu and its derivatives asantimalarials.A new sesquiterpene lactone-Qinghaosu[J].Chinese Sci Bull,1977,22:142.
[10]Borstnik K,Paik I h,Shapiro Y A,et al.Antimalarial chemotherapeutic peroxides:artemisinin,yingzhaosu A and related compounds[J].Int J Parasitol,2002,32(13):1661-1667.
[11]李英.青蒿素研究[M].上海:上海科学技术出版社,2007:6.
[12]李英,虞佩琳,陈一心等.青蒿素衍生物的合成[J].科学通报,1979,24:667-669.
[13]李英,虞佩琳,陈一心等.青蒿素类似物的研究Ⅰ.还原青蒿素的醚类、羧酸酯类及碳酸酯类衍生物的合成[J].药学学报,1981,16(6):429-439.
[14]李英,虞佩琳,陈一心等.青蒿素类似物的研究Ⅱ.应用高效酰化催化剂DMAP 合成双氢青蒿素的羧酸酯类及碳酸酯类衍生物[J].化学学报,1982,40:557-561.
[15]顾浩明,吕宝芬,瞿志祥.青蒿素衍生物对伯氏疟原虫抗氯喹株抗疟活性[J].中国药理学报,1980,1(1):48-50.
[16]刘旭.抗疟药青蒿虎酯的研究[J].药学进展,1999,23(1):46-52.
[17]刘旭.青蒿琥酯的研究进展[J].中国新药杂志,2006,15(22):1918-1923.
[18]梁洁,李英.青蒿素芳香醚类衍生物的合成[J].中国药物化学杂志,1996,6(1):22-25.
[19] Ridley RG Medical need, scientific opportunity, and the drive for antimalarial drugs[J]. Nature, 2002, 415:686-693.
[20] Thomas GB, James OP. Neurotoxicity in animals due to arteether and artemether [J]. Trans R Soc Trop Med Hyg, 1994, 88(Suppl 1): 33-36.
[21] Petras JM, Kyle DE, Gettayacamin M, et al. Arteether: risks of two-week administration in Macaca mulatto[J]. Am J Trop Med Hyg, 1997, 56: 390.
[22] Woo SH, Parker MH, Ploypradith P, et al. Direct conversion of pyranose anomeric OH→F→R in the artemisinin family of antimalarial trioxanes[J].Tetrahedron Lett, 1998, 39(12):1533-1536.
[23] Bishop LPD, Maggs JL, O'Neill PM, et al. The metabolism of arteflene (Ro 42-1611), an endoperoxide antimalarial in rats[J]. Br J Clin Pharmacol, 1998,46:293P.
[24] Ma JY, Katz E, Kyle ED, et al. Syntheses and antimalarial activities of 10-substituted deoxoartemisinins [J]. J Med Chem, 2000, 43(22): 4228-4232.
[25] O'Neill PM, Searle LM, Kan KW, et al. Novel, potent, semisynthetic antimalarial carba analogues of the first-generation 1,2,4-Trioxane artemether[J]. J Med Chem,1999, 42(26): 5487-5493.
[26] Posner GH, Parker MH, Northrop J, et al. Orally active, hydrolytically stable,semisynthetic, antimalarial trioxanes in the artemisinin family[J]. J Med Chem,1999,42(2):300-304.
[27] Chorki F, Grellepois F, Crousse B, et al. First synthesis of 10 alpha-(trifluoromethyl) deoxoartemisinin[J]. Org Lett, 2002, 4(5):757-759.
[28] Chorki F, Crousse B, Bonnet-Delpon D, et al. C-10-Fluorinated derivatives of dihydroartemisinin: difluoromethylene ketones[J]. Tetrahedron Lett, 2001, 42(8):1487-1489.
[29] Jung M, Lee S. Stability of acetal and non acetal-type analogues of artemisinin in simulated stomach acid[J]. Bioorg Med Chem Letters, 1998, 8:1003-1006.
[30] Lin AJ, Li LQ, Klayman DI. Antimalarial activity of new water-soluble dihydroartemisinin derivatives. 3. Aromatic amine analogues[J]. J Med Chem,1990, 33(9):2610-2614.
[31]Grellepois F, Chorki F, Oure'vitch M, et al. Allylic bromination of anhydrodihydroartemisinin and of its 10-trifluoromethyl analogue: a new access to 16-substituted Artemisinin derivatives [J]. Tetrahedron Lett, 2002,43(43):7837-7840.
[32]Yang YH,Li Y,Shi YL,et al.Artemisinin derivates with 12-aniline substitution sythesis and antimalarial activity[J].Bioorg Med Chem Lett,1995,16(5):1791-1794.
[33]Liao XB,Han JY,Li Y.Michael addition of artemisitene[J].Tetrahedron Lett,2001,42(15):2843-2845.
[34]Ma JY,Weiss E,Kyle DE,et al.Acid catalyzed michael additions to artemisitene[J].Bioorg Med Chem Lett,2000,10(14):1601-1603.
[35]Paitayatat S,Tarachompoo B.Thebtaranonth Y.Correlation of antimalarial activity of artemisinin derivntives with binding affinity with ferroprotoporphyrin[J].J Med Chem,1997,40(5):633-638.
[36]Jung M,Li X,Bustos DA,et al.Synthesis and antimalarial activity of (+)-deoxoartemisinin[J].J Med Chem,1990,33(5):1516-1518.
[37]Rong YJ,Wu YL.Synthesis of C-4-substituted qinghaosu analogues[J].J Chem Soc[Perkin 1],1993,18:2147-2148.
[38]叶斌,吴毓林,李国福等.脱羰青蒿素的抗疟活性[J].药学学报,1991 26(3):228-230.
[39]Avery MA,Mehrota S,et al.Structure-activity relationships of the antimalarial agent Artemisinin.4.Effect of substitution at C-3[J].J Med Chem,1996,39(15):2900-2906.
[40]Avery MA,Mehrota S,Johnson TL,et al.Structure-activity relationships of the antimalarial agent artemisinin.5.Analogs of 10-deoxoartemisinin Substituted at C-3 and C-9[J].J Med them,1996,39(21):4149-4155.
[41]Han J,Lee JG,Min SS,et al.Synthesis of new artemisinin analogues from artemisinic acid modified at C-3 and C-13 and their antimalarial activity[J].J Nat Prod,2001,64(9):1201-1205.
[42]Torok DS,Ziffer H,Meshnick SR,et al.Synthesis and antimalarial activity of N-substituted 11-Azaaremisinins[J].J Med Chem,1995,38(26):5045-5050.
[43]Rong YJ,Wu YL.Synthesis of steroidal 1,2,4-trioxane as potential antimalarial agent[J].J Chem Soc[Perkin 1],1993,(18):2149-2150.
[44]Ye B,Wu YL.Synthesis of carba-analogues of qinghaosu[J].Tetrahedron,1989,45(23):7287-7290.
[45]Ye B,Wu YL.An efficient synthesis of qinghaosu and deoxoqinghaosu from arteannuic acid[J].J Chem Soc Chem Commun,1990,10:726.
[46]Avery MA,Gao FL,Chong WKM,et al.Synthesis,comformational analysis,and antimalarial activity of tricyclic analogs of artemisinin[J].Tetrahedron,1994,50(4):957-972.
[47]Flippen-Anderson JL,George C,Gilardi R,et al.Structure of an ether dimer of deoxydihydroqinghaosu,a potential metabolite of the antimalarial arteether[J].Acta Crystallogr C,1989,45(Pt 2):292-294.
[48]Beekman AC,Barentsen AR,Woerdenbag HJ,et al.Stereochemistry-dependent cytotoxicity of some artemisinin derivatives[J].J Nat Prod,1997,60(4):325-330.
[49]Posner GH,Ploypradith P,Parker MH,et al.Antimalarial,antiproliferative,and antitumor activities of artemisinin-derived,chemically robust,trioxane dimers[J].J Med Chem,1999,42(21):4275-4280.
[50]Posner GH,Northrop J,Paik LH,et al.New chemical and biological aspects of artemisinin-derived trioxane dimers[J].Bioorg Med Chem,2002,10(1):227-232.
[51]Posner GH,Paik LH,Sur S,et al.Antimalarial,anticancer,artemisinin-derived trioxane dimers with high stability and efficacy[J].J Med Chem,2003,46(6):1060-1065.
[52]China cooperative research group on Qinghaosu and its derivatives as antimalarials.The chemistry and synthesis of qinghaosu derivatives[J].J Tradit Chin Med,1982,2(1):9-16.
[53]陈一心,虞佩琳,李英等.青蒿素类似物的研究Ⅲ.二氢青蒿素二元酸酯和单酯类衍生物的合成[J].药学学报,1985,20(2):105-111.
[54]陈一心,虞佩琳,李英等.青蒿素类似物的研究Ⅶ.双(二氢青蒿素)醚和双(二氢脱氧青蒿素)醚类衍生物的合成[J].药学学报,1985,20(6):470-473.
[55]Jung M,Lee SM,Ham J,et al.Antitumor activity of novel deoxoartemisinin monomers,dimers,and trimer[J].J Med Chem,2003,46(6):987-994.
[56]Ekthawatchai S,Kamchonwongpaisan S,Tamchompo B,et al.C-16 artemisinin derivatives and their antimalarial and cytotoxic activities:syntheses of artemisinin[J].J Med Chem,2001,44(26):4688-4695.
[57]O'Neill PM,Posner GH.A medicinal chemistry perspective on artemisinin and related endoperoxides[J].J Med Chem,2004,47(12):2945-2964.
[58]Jefford CW.Why artemisinin and certain synthetic peroxides are potent antimalarials.Implications for the mode of action[J].Curr Med Chem,2001,8(15):1803-1826.
[59]Cumming JN,Polypradith P,Posner GH.Antimalarial activity of artemisinin (qinghaosu) and related trioxanes:mechanisms of action[J].Adv Pharmacol, 1997,37:253-297.
[60]Wu YK.How might qinghaosu(artemisinin) and related compounds kill the intraerythrocytic malaria parasite? A chemist's view[J].Acc Chem Res,2002,35(5):255-259.
[61]Posner GH,Oh CH,Milhous WK.Olefin oxidative cleavage and dioxetane formation using triethylsilyl hydrotrioxide:applications to preparation of potent antimalarial 1,2,4-trioxanes[J].Tetrahedron Lett,1991,32(34):4235-4238.
[62]Posner GH,Oh CH,Milhous WK.Extraordinarily potent antimalarial compound:New,structurally simple,easily synthesized,tricyclic 1,2,4-trioxanes[J].J Med Chem,1992,35(13):2459-2467.
[63]Posner GH,Cumming JN,Woo SH,et al.Orally active antimalarial 3-substituted trioxanes:New synthetic methodology and biological evaluation[J].J Med Chem,1998,41(6):940-951.
[64]易天,史震旦,秦东光等.无C环青蒿素类似物的合成研究[J].化学学报,2000,58(4):448-453.
[65]Jefford CW,Rossier JC,Milhous WK.The structure and antimalarial activity of some 1,2,4-trioxanes,1,2,4,5-tetroxanes,and bicyclic endoperoxides.Implications for the mode of action[J].Heterocycles,2000,52(3):1345-1350.
[66]Vennerstrom JL,Fu HN,Ellis WY,et al.Dispiro-1,2,4,5-tetraoxanes:a new class of antimalarial peroxides[J].J Meal Chem,1992,35(16):3023-3027.
[67]Dong YX,Matile H,Chollet J,et al.Synthesis and antimalarial activity of sixteen dispiro- 1,2,4,5-tetraoxanes:alkyl-substituted 7,8,15,16-tetraoxadispiro [5.2.5.2]hexadecanes[J].J Med Chem,2000,43(14):2753-2758.
[68]Dong YX,Matile H,Chollet J,et al.Synthesis and antimalarial activity of 11dispiro-1,2,4,5-tetraoxane analogs of WR 148999.7,8,15,16-Tetraoxadispiro [5.2.5.2]hexadecanes substituted at the 1 and 10 positions with unsaturated and polar functional groups[J].J Med Chem,1999,42(8):1477-1480.
[69]Kim HS,Nagai Y,Ono K,et al.Synthesis and Antimalarial Activity of Novel Medium-Sized 1,2,4,5-Tetraoxacycloalkanes[J].J Med Chem,2001,44(14):2357-2361.
[70]Borstnik K,Paik IH,Shapiro TA,et al.Antimalarial chemotherapeutic peroxides:artemisinin,yingzhaosu A and related compounds[J].Int J Parasitol,2002,32:1661-1667.
[71]Imakura Y,Hachiya K,Ikemoto T,et al.Antimalarial artemisinin analogs: sythesis of 2, 3-desethano-12-deoxoartemisinin related compounds[J].Heterocycles, 1990, 23 (12): 2125-2129.
[72] Posner GH, O'Dowd H, Ploypradith P, et al. Antimalarial cyclic peroxy ketals[J].J Med Chem, 1998,41(12):2164-2167.
[73] Griesbaum K, Ovez B, Huh TS, et al. (?)zonolyses of 02 methyloximes in the presence of acid derivatives: a new access to substitued ozonides [J]. Liebigs Ann,1995,8:1571-1574.
[74] Vennerstrom JL, Arbe-Barnes S, Brun R, et al. Identification of an antimalarial synthetic trioxolane drug development candidate[J]. Nature, 2004,430(7002): 900-904.
[75] China cooperative research group on qinghaosu and its derivatives as antimalarials. Chemical studies on qinghaosu(artemisinin) [J]. J Tradit Chin Med,1982, 2:3-8.
[76] Han LP, Qu LB, Liu TW, et al. Comparative investigation of QHS and DQHS with density functional theory[J]. Chinese J Struc Chem, 2005, 24(5):531-536.
[77] O'Neill PM, Bray PG, Hawley SR, et al. 4-Aminoquinolines-past, present, and future: a chemical perspective[J]. Pharmacol Ther, 1998, 77(1):29-58.
[78] Barnes KI, White NJ. Population biology and antimalarial resistance: The transmission of antimalarial drug resistance in Plasmodium falciparum[J]. Acta Trop, 2005, 94(3):230-240.
[79] Simpson JA, Aarons L, Collins WE, et al. Population dynamics of untreated Plasmodium falciparum malaria within the adult human host during the expansion phase of the infection[J]. Parasitology, 2002,124(Pt 3):247-263.
[80] Day KP, Hayward RE, Dyer M. The biology of Plasmodium falciparum transmission stages[J]. Parasitology, 1998, 116: S95-S109.
[81] Olliaro PL, Haynes RK, Meunier B, et al. Possible modes of action of the artemisinin-type compounds[J]. Trends Parasitol, 2001,17(3):122-126.
[82] Geary TG, Divo AA, Jensen JB. Stage specific actions of antimalarial drugs on Plasmodium falciparum in culture[J]. Am J Trop Med Hyg, 1989,40(3): 240-244.
[83] Ter KF, White NJ, Holloway P, et al. Plasmodium falciparum: in vitro studies of the pharmacodynamic properties of drugs used for the treatment of severe malaria[J]. Exp Parasitol, 1993, 76(l):85-95.
[84] Skinner TS, Manning LS, Johnston WA, et al. In vitro stage-specific sensitivity of Plasmodium falciparum to quinine and artemisinin drugs[J]. Int J Parasitol, 1996,26(5):519-525.
[85] Chen PQ, Li GQ, Guo XB, et al. The infectivity of gametocytes of Plasmodium falciparum from patients treated with artemisinin[J]. Chin Med J(Engl.), 1994,107(9):709-711.
[86] Goldberg DE, Slater AFG, Cerami A, et al. Hemoglobin degradation in the malaria parasite Plasmodium. falciparum: an ordered process in a unique organelle[J]. Proc Natl Acad Sci U S A, 1990, 87(8):2931-2935.
[87] Halliwell B and Gutteridge JMC. Free Radicals in Biology and Medicine[M].Oxford: Clarendon Press, 1989:219.
[88] Meshnick S R, Thomas A, Ranz A, et al. Artemisinin (qinghaosu): the role of intracellular hemin in its mechanism of antimalarial action[J]. Mol Biochem Parasitol, 1991,49(2): 181-189.
[89] Zhang F, Gosser DKJr, Meshnick SR. Hemin-catalyzed decomposition of artemisinin (qinghaosu)[J]. Biochem Pharmacol, 1992, 43(8):1805-1809.
[90] Krungkrai SR, Yuthavong Y. The Antimalarial Action on Plasmodium falciparum of qinghaosu and artesunate in combination with agents which modulate oxidant stress[J]. Trans R Soc Trop Med Hyg, 1987, 81(5): 710-714.
[91] Meshnick SR, Yang YZ, Lima V, et al. Iron-dependent free radical generation from the antimalarial agent artemisinin (qinghaosu)[J]. Antimicrob Agents Chemother, 1993,37(5): 1108-1114.
[92] Levander OA, Ager ALJr, Morris VC, et al. Qinghaosu, dietary vitamin E,selenium, and cod-liver oil: effect on the susceptibility of mice to the malarial parasite Plasmodium yoelii[J]. Am J Clin Nutr, 1989, 50[2]:346-352.
[93] Wu WM, Yao ZJ, Wu YL, et al. Ferrous ion induced cleavage of the peroxy bond in qinghaosu and its derivatives and the DNA damage associated with this process[J]. Chem Commun(Cambridge), 1996,18: 2213-2214.
[94] Posner GH, Oh CH. A regiospecifically oxygen-18 labeled 1, 2, 4-trioxane: a simple chemical model system to probe the mechanism(s) for the antimalarial activity of artemisinin (qinghaosu)[J]. J Am Chem Soc, 1992, 114(21):8328-8329.
[95] Jefford CW, Favarger F, Vicente MGH, et al. The decomposition of cis-fused cyclopenteno-1, 2, 4-trioxanes induced by ferrous salts and some oxophilic reagents [J]. Helv Chim Acta, 1995, 78(2): 452-458.
[96] Jefford CW, Vicente MGH, Jacquier Y, et al. The deoxygenation and isomerization of artemisinin and artemether and their relevance to antimalarial action[J]. Helv Chim Acta, 1996, 79(5): 1475-1487.
[97] Posner GH, Oh CH, Wang D, et al. Mechanism-based design, synthesis, and in-vitro antimalarial testing of new 4-methylated trioxanes structurally related to artemisinin. The importance of a carbon-centered radical for antimalarial activity[J]. J Med Chem, 1994, 37(9):1256-1258.
[98] Wang DY, Wu YL, Wu Y, et al. Further evidence for the participation of primary carbon-centered free radicals in the antimalarial action of the qinghaosu (artemisinin) series of compounds[J]. J Chem Soc [Perkin 1], 2001, 6: 605-609.
[99] Wu WM, Wu YK, Wu YL, et al. Unified mechanistic framework for the Fe(II)-induced cleavage of qinghaosu and derivatives/analogues. The first spin trapping evidence for the previous postulated secondary C-4 radical[J]. J Am Chem Soc, 1998, 120(14): 3316-3325.
[100] O'Neill PM, Bishop LP, Searle NL, et al. Biomimetic Fe(II)-mediated degradation of arteflene (Ro-42-1611).The first EPR spin-trapping evidence for the previously postulated secondary carbon-centred cyclohexyl radical[J]. J Org Chem, 2000, 65(5): 1578-1582.
[101] Butler AR, Gilbert BC, Hulme P, et al. EPR evidence for the involvement of free radicals in the iron-catalysed decomposition of qinghaosu (artemisinin) and some derivatives; antimalarial action of some polycyclic endoperoxides[J]. Free Radical Research, 1998, 28(5): 471-476.
[102] Gu JD, Chen KX, Jiang HL, et al. The Radical transformation in artemisinin: A DFT Study[J]. Journal of Physical Chemistry A, 1999, 103(46): 9364-9369.
[103] Wu Yk, Yue ZY, Wu YL. Interaction of qinghaosu ( artemisinin) with cysteine sulfhydryl mediated by traces of non-heme iron[J]. Angew Chem Int Ed Engl,1999, 38(17): 2580-2582.
[104] Wu Yk, Yue ZY, Liu HH. New insights into the degradation or qinghaosu (artemisinin) mediated by non-heme-iron chelates, and their relevance to the antimalarial mechanism[J]. Helv Chim Acta, 2001, 84(4): 928-932.
[105] Stocks PA, Bray PG, Barton VE, et al. Evidence for a common non-heme chelatable-iron-dependent activation mechanism for semisynthetic and synthetic endoperoxide antimalarial drugs[J]. Angew Chem Int Ed Engl, 2007,46(33):6278-6283.
[106] Haynes RK, Vonwiller SC. The behaviour of qinghaosu (artemisinin) in the presence of non-heme iron(II) and (III) [J]. Tetrahedron Lett, 1996, 37(2): 257-260.
[107] Avery MA, Fan P, Karle JM, et al. Structure-activity relationships of the antimalarial agent artemisinin. 3. Total synthesis of (+)-13-Carbaartemisinin and related tetra- and tricyclic Structures[J]. J Med Chem, 1996, 39(9):1885-1897.
[108] Haynes RK, Ho WY, Chan HW, et al. Highly antimalaria-active artemisinin derivatives: biological activity does not correlate with chemical reactivity[J].Angew Chem Int Ed Engl, 2004,43(11):1381-1385.
[109] Posner GH, Cumming JN, Ploypradith P, et al. Evidence for Fe(IV) = O in the molecular mechanism of action of the trioxane antimalarial artemisinin[J]. J Am Chem Soc, 1995, 117(22): 5885-5886.
[110] Traylor TG, Miksztal AR. Mechanism of hemin-catalyzed epoxidations: electron transfer from alkenes[J]. J Am Chem Soc, 1987,109(9): 2770-2774.
[111] Barton DHR, Martell AE, Sawyer DT. Dioxygen and homogeneous catalytic oxidation[M]. New York: Plenum Press, 1993:183.
[112] Posner GH, Park BS, Gonza'lez L, et al. Evidence for the importance of high-valent Fe=O and of a diketone in the molecular mechanism of action of antimalarial trioxane analogs of artemisinin[J]. J Am Chem Soc, 1996, 118(14):3537-3538.
[113] Kapetanaki S, Varotsis C. Ferryl-oxo heme intermediate in the antimalarial mode of action of artemisinin[J]. FEBS Lett, 2000,474(2-3): 238-241.
[114] Kapetanaki S, Varotsis C. Fourier transform infrared investigation of non-heme Fe(III) and Fe(II) decomposition of artemisinin and of a simplified trioxane alcohol[J]. J Med Chem, 2001,44(19): 3150-3156.
[115] Hufford CD, Lee I, ElSohly HN, et al. Structure elucidation and thermospray high-performance liquid chromatography/mass spectrscopy (HPLC/MS) of the microbial and mammalian metabolites of the antimalarial arteether[J]. Pharm Res, 1990, 7(9): 923-927.
[116] Haynes RK, Pai HH, Voerste A. Ring opening of artemisinin (Qinghaosu) and dihydroartemisinin and interception of the open hydroperoxides with formation of N-Oxidess.A chemical model for antimalarial mode of action[J]. Tetrahedron Lett, 1999,40(25): 4715-4718.
[117] Haynes RK, Vonwiller SC. The Behaviour of Qinghaosu(Artemisinin) in the Presence of Heme Iron(II) and (III) [J].Tetrahedron Lett, 1996, 37(2): 253-256.
[118] Szpilman AM, Korshin EE, Hoos R, et al. Iron(II)-Induced Degradation of Antimalariaip-Sulfonyl Endoperoxides. Evidence for the Generation of Potentially Cytotoxic Carbocations[J]. J Org Chem, 2001, 66(20):6531-6540.
[119] Robert A, Dechy-Cabaret O, Cazelles J ,et al. From mechanistic studies on artemisinin derivatives to new modular antimalarial drugs[J]. Acc Chem Res,2002, 35(3):167-174.
[120] Drew MGB, Metcalfe J, Dascombe MJ, et al. Reactions of artemisinin and arteether with acid: Implications for stability and mode of antimalarial action[J].J Med Chem, 2006,49(20):6065-6073.
[121] Ellis DS, Li ZL, Gu HM, et al. The chemotherapy of rodent malaria. XXXIX.Ultrastructural changes following treatment with artemisinine of Plasmodium berghei infection in mice, with observations of the localization of [~3H]-dihydroartemisinine in P. falciparum in vitro[J]. Ann Trop Med Parasitol,1985, 79(4):367-374.
[122] Maeno Y, Toyoshima T, Fujioka H, et al. Morphologic effects of artemisinin in Plasmodium falciparum[J]. Am J Trop Med Hyg, 1993,49(4): 485-491.
[123] Scott MD, Meshnick SR, Williams RA, et al. Qinghaosu-mediated oxidation in normal and abnormal erythrocytes[J]. J Lab Clin Med, 1989, 114(4):401-406.
[124] Meshnick SR, Tsang TW, Lin FB, et al. Activated oxygen mediates the antimalarial activity of qinghaosu[J]. Prog Clin Biol Res, 1989, 313: 95-104.
[125] Wei NM, Sadrzadeh HSM. Enhancement of hemin-induced membrane damage by artemisinin[J]. Biochem Pharmacol, 1994,48(4): 737-741.
[126] Kawai S, Kano S, Suzuki M. Morphologic effects of artemether on Plasmodium falciparum in Aotus trivirgatus[J]. Am J Trop Med Hyg, 1993, 49(6): 812-818.
[127] Jiang JB, Jacobs G, Liang DS, et al. Qinghaosu-induced changes in the morphology of Plasmodium. falciparum[J]. Am J Trop Med Hyg, 1985,34(3):424- 428.
[128] Ittarat I, Asawamahasakda W, Meshnick SR, et al. The effects of antimalarials on the Plasmodium falciparum dihydroorotate dehydrogenase[J]. Exp Parasitol,1994, 79(1):50-56.
[129] Li W, Mo WK, Shen D, et al. Yeast model uncovers dual roles of mitochondria in the action of artemisinin[J]. PLoS Genet, 2005, 1(3):329-334.
[130] Robert A, Coppel Y, Meunier B. Interaction of artemisinin(Qinghaosu) with the tetraphenylporphyrinato manganese(II) complex[J]. C R Acad Sci Ser IIb: Mec,Phys, Chim, Astron, 1997, 324(1): 59-66.
[131] Robert A, Coppel Y, Meunier B. Alkylation of heme by the antimalarial drug artemisinin[J]. Chem Commun(Cambridge), 2002, (5):414-415.
[132] Hong YL, Yang YZ, Meshnick SR. The interaction of artemisinin with malarial hemozoin[J]. Mol Biochem Parasitol, 1994,63(1):121-128.
[133] Robert A, Meunier B. Is alkylation the main mechanism of action of the antimalarial drug artemisinin?[J] Chem Soc Rev, 1998,27(4):273-279.
[134] Robert A, Meunier B. Alkylating properties of antimalarial artemisinin derivatives and synthetic trioxanes when activated by a reduced heme model[J].Chem-EurJ, 1998, 4(7):1287-1296.
[135] Robert A, Cazelles J, Meunier B. Characterization of the alkylation product of heme by the drug artemisinin[J]. Angew Chem Int Ed Engl, 2001,40(10):1954-1957.
[136] Robert A, Benoit-Vical F, Claparols C, et al. The antimalarial drug artemisinin alkylates heme in infected mice[J]. Proc Natl Acad Sci U S A, 2005, 102(38): 13676-13680.
[137] Benoit-Vical F, Robert A, Meunier B. In vitro and in vivo potentiation of artemisinin and synthetic endoperoxide antimalarial drugs by metalloporphyrins[J]. Antimicrob Agents Chemother, 2000, 44(10):2836-2841.
[138] Cazelles J, Robert A, Meunier B. Alkylating capacity and reaction products of antimalarial trioxanes after activation by a heme model[J]. J Org Chem, 2002,67(3):609-619.
[139] Cazelles J, Camuzat-Dedenis B, Provot O, et al. Alkylating properties of synthetic trioxanes related to artemisinin[J]. J Chem Soc [Perkin 1],1(8):1265-1270.
[140] Provot O, Camuzat-Dedenis B, Hamzaoui M, et al. Structure-activity relationships of synthetic tricyclic trioxanes related to artemisinin: the unexpected alkylative property of a 3-(methoxymethy) analog[J]. European J OrgChem, 1999, 8, 1935-1938.
[141] Sumpan P, Bongkoch T,Yodhathai T, et al.Correlation of antimalarial activity of artemisinin derivatives with binding affinity with ferroprotoporphyrin IX[J]. J Med Chem, 1997, 40(5):633-638.
[142] Robert A, Benoit-Vical F, Dechy-Cabaret O, et al. From classical antimalarial drugs to new compounds based on the mechanism of action of artemisinin[J].Pure Appl Chem, 2001, 73(7):1173-1188.
[143] Slater AFG, Cerami A. Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites[J]. Nature, 1992, 355(6356): 167-169.
[144] Slater AFG, Swiggard WJ, Orton BR, et al. An iron-carboxylate bond links the heme units of malaria pigment [J], Proc Natl Acad Sci U S A, 1991,88(2):325-329.
[145] Pandey AV, Tekwani BL, Singh RL, et al. Artemisinin, an endoperoxide antimalarial, disrupts the hemoglobin catabolism and heme detoxification systems in malarial parasite[J]. J Biol Chem, 1999, 274(27):19383-19388.
[146] Kannan R, Kumar K, Sahal D, et al. Reaction of artemisinin with hemoglobin: Implications for antimalarial activity[J]. Biochemical Journal, 2005,385(2):409-418.
[147] Kannan R, Sahal D, Chauhan VS. Heme-artemisinin adducts are crucial mediators of the ability of artemisinin to inhibit heme polymerization[J]. Chem Biol, 2002,9(3):321-332.
[148] Bray PG, Ward SA, O'Neill PM. Quinolines and artemisinin: chemistry, biology and history[J]. Curr Top Microbiol Immunol, 2005, 295: 3-38.
[149] Stahel E, Druilhe P, Gentilini M. Antagonism of chloroquine with other antimalarials[J]. Trans R Soc Trop Med Hyg, 1988, 82(2):221.
[150] Haynes RK, Monti D, Taramelli D. Artemisinin antimalarials do not inhibit hemozoin formation[J]. Antimicrob Agents Chemother, 2003, 47(3): 1175.
[151] Asawamahasakda W, Ittarat I, Chang CC, et al. Effects of antimalarials and protease inhibitors on plasmodial hemozoin production[J]. Mol Biochem Parasitol, 1994, 67(2):183-191.
[152] Cazelles J, Robert A, Meunier B. Characterization of the main radical and products resulting from a reductive activation of the antimalarial Arteflene (Ro-42-1611)[J]. J Org Chem, 1999, 64(18): 6776-6781.
[153] O'Neill PM, Bishop LP, Searle NL, et al. The biomimetic iron-mediated degradation of Arteflene (Ro-42-1611), an endoperoxide antimalarial:Implications for the mechanism of antimalarial activity[J]. Tetrahedron Lett,1997, 38(24):4263-4266.
[154] Eckstein-Ludwig U, Webb RJ, van Goethem IDA, et al. Artemisinins target the SERCA of Plasmodiumfalcipamm[J]. Nature, 2003, 424(6951): 957-961.
[155] Parapini S, Basilico N, Mondani M, et al. Evidence that haem iron in the malaria parasite is not needed for the antimalarial effects of artemisinin[J]. FEBS Lett, 2004, 575(1-3):91-94.
[156] Atkins PW. Physical Chemistry[M]. Oxford: Oxford University Press, 1994:846-856.
[157] Atamna H, Ginsburg H. The malaria parasite supplies glutathione to its host cell Investigation of glutathione transport and metabolism in human erythrocytes infected with Plasmodiumfalciparum[J]. Eur J Biochem, 1997, 250(3):670-679.
[158] Linares GE, Rodriguez JB. Current status and progresses made in malaria chemotherapy[J]. Curr Med Chem, 2007,14(3):289-314.
[159] Ginsburg H, Famin O, Zhang J, Krugliak M. Inhibition of glutathione-dependent degradation of heme by chloroquine and amodiaquine as a possible basis for their antimalarial mode of action[J]. Biochem Pharmacol, 1998, 56(10):1305-1313.
[160] Famin O, Krugliak M, Ginsburg H. Kinetics of inhibition of glutathione-mediated degradation of Ferriprotoporphyrin IX by antimalarial drugs[J]. Biochem Pharmacol, 1999, 58(1): 59-68.
[161] Wang DY, Wu YL. A possible antimalarial action mode of qinghaosu (artemisinin) series compounds. Alkylation of reduced glutathione by C-centered primary radicals produced from antimalarial compound qinghaosu and 12- (2,4-dimethoxyphenyl)-12-deoxoqinghaosu[J]. Chem Commun(Camb),2000,22:2193-2194.
[162] Wu YL, Chen HB, Jiang K, et al. Interaction of biomolecules with qinghaosu (artemisinin) and its derivatives in the presence of ferrous ion-an exploration of antimalarial mechanism[J]. Pure Appl Chem, 1999, 71(6): 1139-1142.
[163] Aboul-Enein HY. Evidence that the antimalarial activity of artemisinin is not mediated via intercalation with nucleotides[J]. Drug Des Deliv, 1989, 4(2):129-133.
[164] Yang YZ, Asawamahasakda W, Meshnick SR. Alkylation of human albumin by the antimalarial artemisinin[J]. Biochem Pharmacol, 1993,46(2): 336-339.
[165] Yang YZ, Little B, Meshnick SR. Alkylation of proteins by artemisinin effects of heme, pH, and drug structure[J]. Biochem Pharmacol, 1994, 48(3):569-573.
[166] Asawamahasakda W, Benakis A, Meshnick SR. The interaction of artemisinin with red cell membranes[J]. J Lab Clin Med, 1994, 123:757-762.
[167] Uhlemann AC, Wittlin S, Matile H, et al. Mechanism of antimalarial action of the synthetic trioxolane RBX11160 (OZ277) [J]. Antimicrob Agents Chemother,2007, 51(2): 667-672.
[168] Uhlemann AC, Cameron A, Eckstein-Ludwig U, et al. A single amino acid residue can determine the sensitivity of SERCAs to artemisinins[J]. Nat Struct Mol Biol,2005,12(7): 628-629.
[169] Jambou R, Legrand E, Niang M, et al. Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6[J]. Lancet, 2005, 366(9501):1960-1963.
[170] Bhisutthibhan J, Pan XQ, Hossler PA, et al. The Plasmodium falciparum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisinin[J]. J Biol Chem, 1998,273 (26):16192-16198.
[171] Raphael P, Takakuwa Y, Manno S, et al. The Plasmodium falciparum translationally controlled tumor protein: subcellular localization and calcium binding[J]. Eur J Cell Biol, 1999, 78 (9):665-670.
[172] Raphael P, Takakuwa Y, Manno S, et al. A cysteine protease activity from Plasmodium falciparum cleaves human erythrocyte ankyrin[J]. Mol Biochem Parasitol, 2000, 110(2): 259-272.
[173] Rosenthal PJ, Sijwali PS, Singh A, et al. Cysteine proteases of malaria parasites:Targets for Chemotherapy[J]. Curr Pharm Des, 2002, 8(18):1659-1672.
[174] Rosenthal PJ. Plasmodium falciparum effects of proteinase inhibitors on globin hydrolysis by cultured malaria parasites[J]. Exp Parasitol, 1995, 80(2): 272-281.
[175] Shenai BR, Sijwali PS, Singh A, et al. Characterization of native and recombinant Falcipain-2, a principal trophozoite cysteine protease and essential hemoglobinase of Plasmodium falciparum[J]. J Biol Chem, 2000, 275(37):29000-29010.
[176] Sijwali PS, Rosenthal PJ. Gene disruption confirms a critical role for the cysteine protease Falcipain-2 in hemoglobin hydrolysis by Plasmodium falciparum[J]. Proc Natl Acad Sci U S A, 2004,101(13): 4384-4389.
[177] Sullivan DJJr, Gluzman IY, Goldberg DE. Plasmodium hemozoin formation mediated by histidine-richproteins[J]. Science, 1996, 271(5246): 219-222.
[178] Choi CY, Cerda JF, Chu HA, et al. Spectroscopic characterization of the heme-binding sites in Plasmodium falciparum histidine-rich protein 2[J].Biochemistry, 1999, 38(51):16916-16924.
[179] Robert A, Benoit-Vical F, Meunier B. The key role of heme to trigger the antimalarial activity oftrioxanes[J].Coord Chem Rev,2005,249(17-18):1927-1936.
[180]徐筱杰,侯廷军,乔学斌等.计算机辅助药物分子设计[M].北京:化学工业出版社,2004:325.
[181]陈健全,迟翰林.药物分子与其受体的快速对接方法研究[J].科学通报,1996,44(11):1161-1165.
[182]李纯莲,王希诚,赵金城.药物分子对接中的构象搜索策略[J].计算机与应用化学,2004,21(2):201-205
[183]Kitchen DB,Decomez H,Furr JR,et al.Docking and scoring in virtual screening for drug discovery:methods and applications[J].Nat Rev Drug Discov,2004,3(11):935-949.
[184]Muegge I,Martin YC.A general and fast scoring function for protein-ligand interactions:A simplified approach[J].J Med Chem,1999,42(5):791-804.
[185]Gohlke H,Hendlich M,Klebe G.Knowledge-based scoring function to predict protein-ligandi nteractions[J].J Mol Biol,2000,295(2):337-356.
[186]Jiang F,Kim SH."Soft docking":matching of molecular surface cubes[J].J Mol Biol,1991,219(1):79-102.
[187]Kuntz ID.Structure-based strategies for drug design and discovery[J].Science,1992,257(5073):1078-1082.
[188]Goodsell DS,Olsen AJ.Automated docking of substrates to proteins by simulated annealing[J].Proteins,1990,8(3):195-202.
[189]Affinity user guide.MSI Inc.San Diego,USA,2002.
[190]Morris GM,Goodsell DS,Halliday RS,et al.Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function[J].J Comput Chem,1998,19(14):1639-1662.
[191]Kuntz ID,Blaney JM,Oatley SJ,et al.A geometric approach to macromolecule-ligand interactions[J].J Mol Biol,1982,161(2):269-288.
[192]Rarey M,Kramer B,Lengauer T,et al.A fast flexible docking method using an incremental construction algorithm[J].J Mol Biol,1996,261(3):470-489.
[193]徐昕,王南钦,吕鑫等.量子化学的研究现状、发展趋势与展望[J].化学进展,1996,8(1):30-42.
[194]Friesner RA.Ab initio quantum chemistry:Methodology and applications[J].Proc Natl Acad Sci U S A,2005,102(19):6648-6653.
[195]Hatree DR.The calculations of atomic structure[M].New York:John Wiley & Sons.1957:10.
[196]笪良国,张倩茹.量子化学计算方法及其在结构化学中的应用[J].淮南师范学院学报,2007,9(3):101-103.
[197]Dewar MJS.The semiempirical approach to chemistry[J].Int J Quantum Chem,1992,44(4):427-447.
[198]Hohenberg P,Kohn W.Inhomogeneous electron gas[J].Phys Rev B,1964,136(3B):864-871.
[199]Thomas LH.The calculation of atomic fields[J].Proc Camb Philol Soc,1927,23:542-548.
[200]Fermi E.Eine statistische methode zur bestimmung einiger eigenschaften des atoms und ihre anwendung auf die theories des periodischen systems der elemente[J].Zeits f.Physik,1928,48(1-2):73-79.
[201]Kohn W,Sham LJ.Self-Consistent Equations Including Exchange and Correlation Effects[J].Phys Rev A,1965,140(4A):1133-1138.
[202]黄美纯.密度泛函理论的若干进展[J].物理学进展,2000,9(3):199-219.
[203]Collins JB,Schleyer PVR,Binkley JS,et al.Self-consistent molecular orbital methods.ⅩⅦ.Geometries and binding energies of second-row molecules.A comparison of three basis sets[J].J Chem Phys,1976,64(12):5142-5151.
[204]Hariharan PC,Pople JA.The influence of polarization functions on molecular orbital hydrogenation energies[J].Theor Chim Acta,1973,28:213-222.
[205]Andzelm J,Wimmer E.Density functional Gaussian-type-orbital approach to molecular geometries,vibrations,and reaction energies[J].J Chem Phys,1992,96(2):1280-1303.
[206]Scuseria GE.Comparison of coupled-cluster results with a hybrid of Hartree-Fock and density functional theory[J].J Chem Phys,1992,95(10):7528-7530.
[207]Hehre WJ,Ditchfield R,Pople JA.Self-consistent molecular orbital methods.Ⅻ.Further extensions of Gaussian-Type basis sets for use in molecular orbital studies of organic molecules[J].J Chem Phys,1972,56(5):2257-2261.
[208]Ditchfield R,Hehre WJ,Pople JA.Self-consistent molecular orbital methods.Ⅸ.An extended Gaussian-Type basis for molecular-orbital studies of organic molecules[J].J Chem Phys,1971,54(2):724-728.
[209]Clark T,Chandrasekhar J,Spitznagel GW,et al.Efficient diffuse function-augmented basis sets for anion calculations.Ⅲ.The 3-21+G basis set for first-row elements,Li-F[J].J Comput Chem,1983,4(3):294-301.
[210]Frisch MJ,Trucks G.W,Schlegel HB,et al.Gaussian 03,Revision B.03;Gaussian Inc.,Pittsburgh,PA,2003.
[211]赵国屏等.生物信息学[M].北京:科学出版社,2004:149.
[212]Anfinsen CB.Principles that govern the folding of protein chains[J].Science,1973,181(96):223-230.
[213]Sternberg MJE,Bates PA,Kelly LA,et al.Progress in protein structure prediction:assessment of CASP3[J].Curr Opin Struct Biol,1999,9(3):368-373.
[214]Philipe B,Helgew W.Structural Bioinformatics[M].New York:John Wiley &Sons Inc,2003:509-512.
[215]Orengo CA,Jones DT,Thornton JM.Protein superfamilies and domain superfolds[J].Nature,1994,372(6507):631-634.
[216]Finkelstein AV,Ptitsyn OB.Why do globular proteins fit the limited set of folding patterns[J].Prog Biophys Mol Biol,1987,50(3):171-190.
[217]RCSB Protein Data Bank.An information portal to biological macromolecular structures[EB/OL].:http://www.rcsb.org/pdb/statistics/contentGrowthChart.do?c ontent=fold-scop,2008-10-07.
[218]蒋彦,王小行,曹毅等.基础生物信息学及应用[M].北京:清华大学出版社,2003:177.
[219]Gardner MJ,Hall N,Fung E,et al.Genome sequence of the human malaria parasite Plasmodiumfalciparum[J].Nature,2002,419(6906):498-511.
[220]Meshnick SR.Artemisinin:mechanisms of action,resistance and toxicity[J].Int J Parasitol,2002,32(12):1655-1660.
[221]Altschul SF,Madden TL,Schaffer AA,et al.Gapped BLAST and PSI-BLAST:a new generation of protein database searchprograms[J].Nucleic Acids Res,1997,25(17):3389-3402.
[222]Braun W,GO N.Calculation of protein conformations by proton-proton distance constraints:A new efficient algorithm[J].J Mol Biol,1985,186(3):611-626.
[223]Krogh A,Brown M,Mian IS,et al.Hidden Markov models in computational biology.Applications to protein modeling[J].J Mol Biol,1994,235(5):1501-1531.
[224]Jung M,Kim H,Nam KY,et al.Three-dimensional structure of Plasmodium falciparum Ca2+-ATPase(PfATP6) and docking of artemisinin derivatives to PfATP6[J].Bioorg Med Chem Letters,2005,15(12):2994-2997.
[225]Sali A,Blundell TL.Comparative protein modelling by satisfaction of spatial restraints[J].J Mol Biol,1993,234(3):779-815.
[226]Toyoshima C,Nomura H,Tsuda T.Lumenal gating mechanism revealed in calcium pump crystal structures with phosphate analogues[J].Nature,2004,432(7015):361-368.
[227]Morris AL,MacArthur MW,Hutchinson EG,et al.Stereochemical quality of protein structure coordinates[J].Proteins,1992,12(4):345-364.
[228]L(u|¨)thy R,Bowie JU,Eisenberg D.Assessment of protein models with three-dimensional profiles[J].Nature,1992,356(6364):83-85.
[229]Colovos C,Yeates TO.Verification of protein structures:patterns ofnonbonded atomic interactions[J].Protein Sci,1993,2(9):1511-1519.
[230]Hooft RWW,Vriend G,Sander C,et al.Errors in protein structures[J].Nature,1996,381(6580):272.
[231]Sanchez JC,Schaller D,Ravier F,et al.Translationally controlled tumor protein:a protein identified in several nontumoral cells including erythrocytes[J].Electrophoresis,1997,18(1):150-155.
[232]傅作申,陈知航,张娟等.恶性疟原虫海南株翻译控制肿瘤蛋白(TCTP)基因在M15中的表达[A].2006中国科协年会论文集[C].北京:中国科学技术协会学会学术部,2006:78-81.
[233]Pontius J,Richelle J,Wodak SJ.Deviations from standard atomic volumes as a quality measure for protein crystal structures[J].J Mol Biol,1996,264(1):121-136.
[234]Lisgarten JN,Potter BS,Bantuzeko C,et al.Structure,absolute configuration,and conformation of the antimalarial compound,Artemisinin[J].J Chem Crystallogr,1998,28(7):539-543.
[235]Sijwali PS,Kato K,Seydel KB,et al.Plasmodiumfalciparurn cysteine protease falcipain-1 is not essential in erythrocytic stage malaria parasites[J].Proc Natl Acad Sci U S A,2004,101(23):8721-8726.
[236]Jeong JJ,Kumar A,Hanada T,et al.Cloning and characterization of Plasmodium falciparum cysteine protease,falcipain-2B[J].Blood Cells Mol Dis,2006,36(3):429-435.
[237]Sijwali PS,Koo J,Singh N,et al.Gene disruptions demonstrate independent roles for the four falcipain cysteine proteases of Plasmodium falciparum[J].Mol Biochem Parasitol, 2006,150(1):96-106.
[238] Hogg T, Nagarajan K, Herzberg S, et al. Structural and functional characterization of Falcipain-2, a hemoglobinase from the malarial parasite Plasmodiumfalciparum[J]. J Biol Chem, 2006, 281(35):25425-25437.
[239] Het(?)nyi C, van der Spoel D. Efficient docking of peptides to proteins without prior knowledge of the binding site[J]. Protein Sci, 2002, 11 (7): 1729-1737.
[240] Jining L, Makagiansar I, Yusuf-Makagiansar H, et al. Design, structure and biological activity of beta-turn peptides of CD2 protein for inhibition of T-cell adhesion[J]. Eur J Biochem, 2004, 271(14):2873-2886.
[241] Espinoza-Fonseca LM. Targeting MDM2 by the small molecule RITA: towards the development of new multi-target drugs against cancer[J]. Theor Biol Med Model, 2005, 2:38.
[242] Sunaga S, Yoshimori A, Shiokawa D, et al. Structure basis for the inhibitory mechanism of a novel DNase gamma-specific inhibitor, DR396[J]. Bioorg Med Chem, 2006,14(12):4217-4226.
[243] Street IP, Armstrong CR, Withers SG Hydrogen bonding and specificity. Fluorodeoxy sugars as probes of hydrogen bonding in the glycogen phosphorylase-glucose complex[J]. Biochemistry, 1986, 25(20):6021-6027.
[244] Fersht AR. Basis of biological specificity[J]. Trends Biochem Sci, 1984,9(4): 145-147.
[245] Fersht AR, Shi JP, Knill-Jones J, et al. Hydrogen bonding and biological specificity analysed by protein engineering[J]. Nature, 1985,314(6008):235-238.
[246] Goh LL, Sim TS. Homology modeling and mutagenesis analyses of Plasmodiumfalciparum falcipain 2A: implications for rational drug design[J].Biochem Biophys Res Commun, 2004, 323(2):565-572.
[247] Berger A, Schechter I. Mapping the active site of papain with the aid of peptide substrates and inhibitors[J]. Philos Trans R Soc Lond B Biol Sci, 1970,257(813):249-264.
[248] Sabnis YA, Desai PV, Rosenthal PJ, et al. Probing the structure of falcipain-3, a cysteine protease from Plasmodiumfalciparum: comparative protein modeling and docking studies[J]. Protein Sci, 2003, 12(3):501-509.
[249] Yamamoto D, Matsumoto K, Ishida T, et al. Crystal structure and molecular conformation of E-64, a cysteine protease inhibitor[J]. Chem Pharm Bull, 1989, 37(10):2577-2581.
[250]Matsumoto K,Mizoue K,Kitamura K,et al.Structural basis of inhibition of cysteine proteases by E-64 and its derivatives[J].Biopolymers,1999,51(1):99-107.
[251]Singh A,Walker KJ,Sijwali PS,et al.A chimeric cysteine protease of Plasmodium berghei engineered to resemble the Plasrnodium falciparum protease falcipain-2[J].Protein Eng Des Sel,2007,20(4):171-177.
[252]Avery MA,Alvim-Gaston M,Rodrigues CR,et al.Structure-activity relationships of the antimalarial agent artemisinin.6.The development of predictive in vitro potency models using CoMFA and HQSAR methodologies[J].J Med Chem,2002,45(2):292-303.
[253]Lin AJ,Klayman DL,Milhous WK.Antimalarial activity of new water-soluble dihydroartemisinin derivatives[J].J Med Chem,1987,30(11):2147-2150.
[254]Avery MA,Bonk JD,Chong WK,et al.Structure-activity relationships of the antimalarial agent artemisinin.2.Effect ofheteroatom substitution at O-11:synthesis and bioassay ofN-alkyl-11-aza-9-desmethylartemisinins[J].J Med Chem,1995,38(26):5038-5044.
[255]Posner GH,Oh CH,Gerena L,et al.Synthesis and antimalarial activities of structurally simplified 1,2,4-trioxanes related to artemisinin[J].Heteroat Chem,1995,6(2):105-116.
[256]Guha R,Jurs PC.Development of QSAR models to predict and interpret the biological activity of artemisinin analogues[J].J Chem Inf Comput Sci,2004,44(4):1440-1449.
[257]Vennerstroml LJ,Arbe-Barnes S,Brun R,et al.Identification of an antimalarial synthetic trioxolane drug development candidate[J].Nature,2004,430:900-904.
[258]Rogers D,Hopfinger AJ.Application of Genetic Function Approximation to Quantitative Structure-Activity Relationships and Quantitative Structure-Property Relationships[J].J Chem Inf Comput Sci,1994,34(4):854-866.
[259]朱杰,季海涛,张万年.进化算法在定量构效关系研究中的应用[J].中国药物化学杂志,1999,9(2):151-156.
[260]Bhisutthibhan J,Meshnick SR.Immunoprecipitation of[~3H]dihy-droartemisinin translationally controlled tumor protein(TCTP) adduct from Plasmodium falciparum infected erythrocytes by using anti-TCTP antibodies[J].Antimicrob Agents Chemother, 2001, 45(8):2397-2399.
[261] Walker DJ, Pitsch J, Peng MM. Mechanisms of artemisinin resistance in the rodent malaria pathogen[J]. Antimicrob Agents Chemother, 2000, 44(2):344-347.
[262] Bommer UA, Thiele BJ. The translation controlled protein (TCTP)[J]. Int J Biochem Cell Biol, 2004, 36:379-385.
[263] MacDonald SM, Rafnar T, Langdon J, et al. Molecular dentification of an IgE-dependenthistamine-releasing factor[J]. Science, 1995, 269: 688-690.
[264]Wellems TE, Howard RJ. Homologous genes encode two distinct histidine-rich proteins in a cloned isolate of Plasmodium falciparum[J]. Proc Natl Acad Sci U S A, 1986, 83(16):6065-6069.
[265] Panton LJ, McPhie P, Maloy WL, et al. Purification and partial characterization of an unusual protein of Plasmodium falciparum: histidine-rich protein II[J].Mol Biochem Parasitol, 1989, 35(2):149-160.
[266] Goh LL, Sim TS. Characterization of amino acid variation at strategic positions in parasite and human proteases for selective inhibition of falcipains in Plasmodium falciparum[J]. Biochem Biophys Res Commun, 2005,335(3):762-770.
[267] Jeong JJ, Kumar A, Hanada T, et al. Cloning and characterization of Plasmodium falciparum cysteine protease, falcipain-2B[J]. Blood Cells Mol Dis,2006, 36(3):429-435.
[268] Dahl EL, Rosenthal PJ. Biosynthesis, localization, and processing of falcipain cysteine proteases of Plasmodium falciparum[J]. Mol Biochem Parasitol, 2005,139 (2):205-212.
[269] Singh N, Sijwali PS, Pandey KC, et al. Plasmodium falciparum: biochemical characterization of the cysteine protease falcipain-2'[J]. Exp Parasitol, 2006,112(3):187-192.
[270] Eksi S, Czesny B, van Gemert GJ, et al. Inhibition of Plasmodium falciparum oocyst production by membrane-permeant cysteine protease inhibitor E64d[J].Antimicrob Agents Chemother, 2007, 51(3):1064-1070.
[271] Guruprasad K, Reddy BV, Pandit MW. Correlation between stability of a protein and its dipeptide composition: a novel approach for predicting in vivo stability of a protein from its primary sequence[J]. Protein Eng, 1990,4(2):155-161.
[272]Kyte J,Doolittle RF.A simple method for displaying the hydropathic character of a protein[J].J Mol Biol,1982,157(1):105-132.
[273]Muskal S M,Holbrook R S,Kim S H.Prediction of the disulfide bonding state of cysteine in proteins[J].Protein Eng(S0269-2139),1990,3:667-672.
[274]Fariselli P,Riccobelli P,Casadio R.Role of evolutionary information in predicting the disulfide-bonding state of cysteine in proteins[J].Proteins (S0887-3585),1999,36:340-346.
[275]Ferre F,Clote P.DiANNA:a web server for disulfide connectivity prediction[J].Nucleic Acids Res,2005,(Web Server issue):W230-232.
[276]Kerr ID,Lee JH,Pandey KC,et al.Structures of falcipain-2 and falcipain-3bound to small molecule inhibitors:implications for substrate specificity[J].J Med Chem,2009,52(3):852-857.
[277]Shi W,Ting LM,Kicska GA,et al.Plasmodium falciparum purine nucleoside phosphorylase:crystal structures,immucillin inhibitors,and dual catalytic function[J].J Biol Chem,2004,279(18):18103-18106.
[278]Schnick C,Robien MA,Brzozowski AM,et al.Structures of Plasmodium falciparurn purine nucleoside phosphorylase complexed with sulfate and its natural substrate inosine[J].Acta Crystallogr D Biol Crystallogr,2005,61(Pt 9):1245-1254.
[279]Robien MA,Nguyen KT,Kumar A,et al.An improved crystal form of Plasmodium falciparum peptide deformylase[J].Protein Sci,2004,13(4):1155-1163.
[280]Kumar A,Nguyen KT,Srivathsan S,et al.Crystals ofpeptide deformylase from Plasmodium falciparum reveal critical characteristics of the active site for drug design[J].Structure,2002,10(3):357-367.
[281]Caruthers J,Bosch J,Buckner F,et al.Structure ofa ribulose 5-phosphate 3-epimerase from Plasmodium falciparum[J].Proteins,2006,62(2):338-342.
[282]Tanaka N,Nakanishi M,Kusakabe Y,et al.Crystal structure of S-adenosyl-L-homocysteine hydrolase from the human malaria parasite Plasmodium falciparum[J].J Mol Biol,2004,343(4):1007-1017.
[283]Holmes MA,Buckner FS,Van Voorhis WC,et al.Structure ofribose 5-phosphate isomerase from Plasmodium falciparum[J].Acta Crystallogr Sect F Struct Biol Cryst Commun,2006,62(Pt 5):427-431.
[284]Hamada K,Ago H,Sugahara M,et al.Oxyanion hole-stabilized stereospecific isomerization in ribose-5-phosphate isomerase (Rpi)[J]. J Biol Chem, 2003,278(49):49183-49190.
[285] Bello AM, Poduch E, Liu Y, et al. Structure-activity relationships of C6-uridine derivatives targeting plasmodia orotidine monophosphate decarboxylase[J]. J Med Chem, 2008,51(3):439-448.
[286] Freundlich JS, Wang F, Tsai HC, et al. X-ray structural analysis of Plasmodium falciparum enoyl acyl carrier protein reductase as a pathway toward the optimization of triclosan antimalarial efficacy[J]. J Biol Chem, 2007,282(35):25436-25444.
[287] Dufe VT, Qiu W, Miiller IB, et al. Crystal structure of Plasmodium falciparum spermidine synthase in complex with the substrate decarboxylated S-adenosylmethionine and the potent inhibitors 4MCHA and AdoDATO[J]. J Mol Biol, 2007, 373(1): 167-177.
[2]WHO Healthe Organization.World Malaria Report 2008[M].2008:9.
[3]李华宪,陈国伟,杨沅川等.云南省2001-2005年疟疾疫情分析[J].中国寄生虫学与寄生虫病杂志,2008,26(1):46-49.
[4]卫疾控发(2006)70号.2006-2015年全国疟疾防治规划[J].中华人民共和国卫生部公报,2006,3:50-53.
[5]周水森,王漪,汤林华.2006年全国疟疾形势[J].中国寄生虫学与寄生虫病杂志,2007,25(6):439-441.
[6]Roger B.Rolling Back Malaria:Rhetoric and Reality in the Fight against a Deadly Killer[EB].AEI,2008-4-24.
[7]Wemsdorfer WH.抗药性疟疾的流行病学[J].国外医学寄生虫病分册,1994,21(5):196-199.
[8]Liu JM,Ni MY,Fan JF,et al.The structure and reaction of Qinghaosu[J].Acta Chim Sinica,1979,37:129-141.
[9]China cooperative research group on Qinghaosu and its derivatives asantimalarials.A new sesquiterpene lactone-Qinghaosu[J].Chinese Sci Bull,1977,22:142.
[10]Borstnik K,Paik I h,Shapiro Y A,et al.Antimalarial chemotherapeutic peroxides:artemisinin,yingzhaosu A and related compounds[J].Int J Parasitol,2002,32(13):1661-1667.
[11]李英.青蒿素研究[M].上海:上海科学技术出版社,2007:6.
[12]李英,虞佩琳,陈一心等.青蒿素衍生物的合成[J].科学通报,1979,24:667-669.
[13]李英,虞佩琳,陈一心等.青蒿素类似物的研究Ⅰ.还原青蒿素的醚类、羧酸酯类及碳酸酯类衍生物的合成[J].药学学报,1981,16(6):429-439.
[14]李英,虞佩琳,陈一心等.青蒿素类似物的研究Ⅱ.应用高效酰化催化剂DMAP 合成双氢青蒿素的羧酸酯类及碳酸酯类衍生物[J].化学学报,1982,40:557-561.
[15]顾浩明,吕宝芬,瞿志祥.青蒿素衍生物对伯氏疟原虫抗氯喹株抗疟活性[J].中国药理学报,1980,1(1):48-50.
[16]刘旭.抗疟药青蒿虎酯的研究[J].药学进展,1999,23(1):46-52.
[17]刘旭.青蒿琥酯的研究进展[J].中国新药杂志,2006,15(22):1918-1923.
[18]梁洁,李英.青蒿素芳香醚类衍生物的合成[J].中国药物化学杂志,1996,6(1):22-25.
[19] Ridley RG Medical need, scientific opportunity, and the drive for antimalarial drugs[J]. Nature, 2002, 415:686-693.
[20] Thomas GB, James OP. Neurotoxicity in animals due to arteether and artemether [J]. Trans R Soc Trop Med Hyg, 1994, 88(Suppl 1): 33-36.
[21] Petras JM, Kyle DE, Gettayacamin M, et al. Arteether: risks of two-week administration in Macaca mulatto[J]. Am J Trop Med Hyg, 1997, 56: 390.
[22] Woo SH, Parker MH, Ploypradith P, et al. Direct conversion of pyranose anomeric OH→F→R in the artemisinin family of antimalarial trioxanes[J].Tetrahedron Lett, 1998, 39(12):1533-1536.
[23] Bishop LPD, Maggs JL, O'Neill PM, et al. The metabolism of arteflene (Ro 42-1611), an endoperoxide antimalarial in rats[J]. Br J Clin Pharmacol, 1998,46:293P.
[24] Ma JY, Katz E, Kyle ED, et al. Syntheses and antimalarial activities of 10-substituted deoxoartemisinins [J]. J Med Chem, 2000, 43(22): 4228-4232.
[25] O'Neill PM, Searle LM, Kan KW, et al. Novel, potent, semisynthetic antimalarial carba analogues of the first-generation 1,2,4-Trioxane artemether[J]. J Med Chem,1999, 42(26): 5487-5493.
[26] Posner GH, Parker MH, Northrop J, et al. Orally active, hydrolytically stable,semisynthetic, antimalarial trioxanes in the artemisinin family[J]. J Med Chem,1999,42(2):300-304.
[27] Chorki F, Grellepois F, Crousse B, et al. First synthesis of 10 alpha-(trifluoromethyl) deoxoartemisinin[J]. Org Lett, 2002, 4(5):757-759.
[28] Chorki F, Crousse B, Bonnet-Delpon D, et al. C-10-Fluorinated derivatives of dihydroartemisinin: difluoromethylene ketones[J]. Tetrahedron Lett, 2001, 42(8):1487-1489.
[29] Jung M, Lee S. Stability of acetal and non acetal-type analogues of artemisinin in simulated stomach acid[J]. Bioorg Med Chem Letters, 1998, 8:1003-1006.
[30] Lin AJ, Li LQ, Klayman DI. Antimalarial activity of new water-soluble dihydroartemisinin derivatives. 3. Aromatic amine analogues[J]. J Med Chem,1990, 33(9):2610-2614.
[31]Grellepois F, Chorki F, Oure'vitch M, et al. Allylic bromination of anhydrodihydroartemisinin and of its 10-trifluoromethyl analogue: a new access to 16-substituted Artemisinin derivatives [J]. Tetrahedron Lett, 2002,43(43):7837-7840.
[32]Yang YH,Li Y,Shi YL,et al.Artemisinin derivates with 12-aniline substitution sythesis and antimalarial activity[J].Bioorg Med Chem Lett,1995,16(5):1791-1794.
[33]Liao XB,Han JY,Li Y.Michael addition of artemisitene[J].Tetrahedron Lett,2001,42(15):2843-2845.
[34]Ma JY,Weiss E,Kyle DE,et al.Acid catalyzed michael additions to artemisitene[J].Bioorg Med Chem Lett,2000,10(14):1601-1603.
[35]Paitayatat S,Tarachompoo B.Thebtaranonth Y.Correlation of antimalarial activity of artemisinin derivntives with binding affinity with ferroprotoporphyrin[J].J Med Chem,1997,40(5):633-638.
[36]Jung M,Li X,Bustos DA,et al.Synthesis and antimalarial activity of (+)-deoxoartemisinin[J].J Med Chem,1990,33(5):1516-1518.
[37]Rong YJ,Wu YL.Synthesis of C-4-substituted qinghaosu analogues[J].J Chem Soc[Perkin 1],1993,18:2147-2148.
[38]叶斌,吴毓林,李国福等.脱羰青蒿素的抗疟活性[J].药学学报,1991 26(3):228-230.
[39]Avery MA,Mehrota S,et al.Structure-activity relationships of the antimalarial agent Artemisinin.4.Effect of substitution at C-3[J].J Med Chem,1996,39(15):2900-2906.
[40]Avery MA,Mehrota S,Johnson TL,et al.Structure-activity relationships of the antimalarial agent artemisinin.5.Analogs of 10-deoxoartemisinin Substituted at C-3 and C-9[J].J Med them,1996,39(21):4149-4155.
[41]Han J,Lee JG,Min SS,et al.Synthesis of new artemisinin analogues from artemisinic acid modified at C-3 and C-13 and their antimalarial activity[J].J Nat Prod,2001,64(9):1201-1205.
[42]Torok DS,Ziffer H,Meshnick SR,et al.Synthesis and antimalarial activity of N-substituted 11-Azaaremisinins[J].J Med Chem,1995,38(26):5045-5050.
[43]Rong YJ,Wu YL.Synthesis of steroidal 1,2,4-trioxane as potential antimalarial agent[J].J Chem Soc[Perkin 1],1993,(18):2149-2150.
[44]Ye B,Wu YL.Synthesis of carba-analogues of qinghaosu[J].Tetrahedron,1989,45(23):7287-7290.
[45]Ye B,Wu YL.An efficient synthesis of qinghaosu and deoxoqinghaosu from arteannuic acid[J].J Chem Soc Chem Commun,1990,10:726.
[46]Avery MA,Gao FL,Chong WKM,et al.Synthesis,comformational analysis,and antimalarial activity of tricyclic analogs of artemisinin[J].Tetrahedron,1994,50(4):957-972.
[47]Flippen-Anderson JL,George C,Gilardi R,et al.Structure of an ether dimer of deoxydihydroqinghaosu,a potential metabolite of the antimalarial arteether[J].Acta Crystallogr C,1989,45(Pt 2):292-294.
[48]Beekman AC,Barentsen AR,Woerdenbag HJ,et al.Stereochemistry-dependent cytotoxicity of some artemisinin derivatives[J].J Nat Prod,1997,60(4):325-330.
[49]Posner GH,Ploypradith P,Parker MH,et al.Antimalarial,antiproliferative,and antitumor activities of artemisinin-derived,chemically robust,trioxane dimers[J].J Med Chem,1999,42(21):4275-4280.
[50]Posner GH,Northrop J,Paik LH,et al.New chemical and biological aspects of artemisinin-derived trioxane dimers[J].Bioorg Med Chem,2002,10(1):227-232.
[51]Posner GH,Paik LH,Sur S,et al.Antimalarial,anticancer,artemisinin-derived trioxane dimers with high stability and efficacy[J].J Med Chem,2003,46(6):1060-1065.
[52]China cooperative research group on Qinghaosu and its derivatives as antimalarials.The chemistry and synthesis of qinghaosu derivatives[J].J Tradit Chin Med,1982,2(1):9-16.
[53]陈一心,虞佩琳,李英等.青蒿素类似物的研究Ⅲ.二氢青蒿素二元酸酯和单酯类衍生物的合成[J].药学学报,1985,20(2):105-111.
[54]陈一心,虞佩琳,李英等.青蒿素类似物的研究Ⅶ.双(二氢青蒿素)醚和双(二氢脱氧青蒿素)醚类衍生物的合成[J].药学学报,1985,20(6):470-473.
[55]Jung M,Lee SM,Ham J,et al.Antitumor activity of novel deoxoartemisinin monomers,dimers,and trimer[J].J Med Chem,2003,46(6):987-994.
[56]Ekthawatchai S,Kamchonwongpaisan S,Tamchompo B,et al.C-16 artemisinin derivatives and their antimalarial and cytotoxic activities:syntheses of artemisinin[J].J Med Chem,2001,44(26):4688-4695.
[57]O'Neill PM,Posner GH.A medicinal chemistry perspective on artemisinin and related endoperoxides[J].J Med Chem,2004,47(12):2945-2964.
[58]Jefford CW.Why artemisinin and certain synthetic peroxides are potent antimalarials.Implications for the mode of action[J].Curr Med Chem,2001,8(15):1803-1826.
[59]Cumming JN,Polypradith P,Posner GH.Antimalarial activity of artemisinin (qinghaosu) and related trioxanes:mechanisms of action[J].Adv Pharmacol, 1997,37:253-297.
[60]Wu YK.How might qinghaosu(artemisinin) and related compounds kill the intraerythrocytic malaria parasite? A chemist's view[J].Acc Chem Res,2002,35(5):255-259.
[61]Posner GH,Oh CH,Milhous WK.Olefin oxidative cleavage and dioxetane formation using triethylsilyl hydrotrioxide:applications to preparation of potent antimalarial 1,2,4-trioxanes[J].Tetrahedron Lett,1991,32(34):4235-4238.
[62]Posner GH,Oh CH,Milhous WK.Extraordinarily potent antimalarial compound:New,structurally simple,easily synthesized,tricyclic 1,2,4-trioxanes[J].J Med Chem,1992,35(13):2459-2467.
[63]Posner GH,Cumming JN,Woo SH,et al.Orally active antimalarial 3-substituted trioxanes:New synthetic methodology and biological evaluation[J].J Med Chem,1998,41(6):940-951.
[64]易天,史震旦,秦东光等.无C环青蒿素类似物的合成研究[J].化学学报,2000,58(4):448-453.
[65]Jefford CW,Rossier JC,Milhous WK.The structure and antimalarial activity of some 1,2,4-trioxanes,1,2,4,5-tetroxanes,and bicyclic endoperoxides.Implications for the mode of action[J].Heterocycles,2000,52(3):1345-1350.
[66]Vennerstrom JL,Fu HN,Ellis WY,et al.Dispiro-1,2,4,5-tetraoxanes:a new class of antimalarial peroxides[J].J Meal Chem,1992,35(16):3023-3027.
[67]Dong YX,Matile H,Chollet J,et al.Synthesis and antimalarial activity of sixteen dispiro- 1,2,4,5-tetraoxanes:alkyl-substituted 7,8,15,16-tetraoxadispiro [5.2.5.2]hexadecanes[J].J Med Chem,2000,43(14):2753-2758.
[68]Dong YX,Matile H,Chollet J,et al.Synthesis and antimalarial activity of 11dispiro-1,2,4,5-tetraoxane analogs of WR 148999.7,8,15,16-Tetraoxadispiro [5.2.5.2]hexadecanes substituted at the 1 and 10 positions with unsaturated and polar functional groups[J].J Med Chem,1999,42(8):1477-1480.
[69]Kim HS,Nagai Y,Ono K,et al.Synthesis and Antimalarial Activity of Novel Medium-Sized 1,2,4,5-Tetraoxacycloalkanes[J].J Med Chem,2001,44(14):2357-2361.
[70]Borstnik K,Paik IH,Shapiro TA,et al.Antimalarial chemotherapeutic peroxides:artemisinin,yingzhaosu A and related compounds[J].Int J Parasitol,2002,32:1661-1667.
[71]Imakura Y,Hachiya K,Ikemoto T,et al.Antimalarial artemisinin analogs: sythesis of 2, 3-desethano-12-deoxoartemisinin related compounds[J].Heterocycles, 1990, 23 (12): 2125-2129.
[72] Posner GH, O'Dowd H, Ploypradith P, et al. Antimalarial cyclic peroxy ketals[J].J Med Chem, 1998,41(12):2164-2167.
[73] Griesbaum K, Ovez B, Huh TS, et al. (?)zonolyses of 02 methyloximes in the presence of acid derivatives: a new access to substitued ozonides [J]. Liebigs Ann,1995,8:1571-1574.
[74] Vennerstrom JL, Arbe-Barnes S, Brun R, et al. Identification of an antimalarial synthetic trioxolane drug development candidate[J]. Nature, 2004,430(7002): 900-904.
[75] China cooperative research group on qinghaosu and its derivatives as antimalarials. Chemical studies on qinghaosu(artemisinin) [J]. J Tradit Chin Med,1982, 2:3-8.
[76] Han LP, Qu LB, Liu TW, et al. Comparative investigation of QHS and DQHS with density functional theory[J]. Chinese J Struc Chem, 2005, 24(5):531-536.
[77] O'Neill PM, Bray PG, Hawley SR, et al. 4-Aminoquinolines-past, present, and future: a chemical perspective[J]. Pharmacol Ther, 1998, 77(1):29-58.
[78] Barnes KI, White NJ. Population biology and antimalarial resistance: The transmission of antimalarial drug resistance in Plasmodium falciparum[J]. Acta Trop, 2005, 94(3):230-240.
[79] Simpson JA, Aarons L, Collins WE, et al. Population dynamics of untreated Plasmodium falciparum malaria within the adult human host during the expansion phase of the infection[J]. Parasitology, 2002,124(Pt 3):247-263.
[80] Day KP, Hayward RE, Dyer M. The biology of Plasmodium falciparum transmission stages[J]. Parasitology, 1998, 116: S95-S109.
[81] Olliaro PL, Haynes RK, Meunier B, et al. Possible modes of action of the artemisinin-type compounds[J]. Trends Parasitol, 2001,17(3):122-126.
[82] Geary TG, Divo AA, Jensen JB. Stage specific actions of antimalarial drugs on Plasmodium falciparum in culture[J]. Am J Trop Med Hyg, 1989,40(3): 240-244.
[83] Ter KF, White NJ, Holloway P, et al. Plasmodium falciparum: in vitro studies of the pharmacodynamic properties of drugs used for the treatment of severe malaria[J]. Exp Parasitol, 1993, 76(l):85-95.
[84] Skinner TS, Manning LS, Johnston WA, et al. In vitro stage-specific sensitivity of Plasmodium falciparum to quinine and artemisinin drugs[J]. Int J Parasitol, 1996,26(5):519-525.
[85] Chen PQ, Li GQ, Guo XB, et al. The infectivity of gametocytes of Plasmodium falciparum from patients treated with artemisinin[J]. Chin Med J(Engl.), 1994,107(9):709-711.
[86] Goldberg DE, Slater AFG, Cerami A, et al. Hemoglobin degradation in the malaria parasite Plasmodium. falciparum: an ordered process in a unique organelle[J]. Proc Natl Acad Sci U S A, 1990, 87(8):2931-2935.
[87] Halliwell B and Gutteridge JMC. Free Radicals in Biology and Medicine[M].Oxford: Clarendon Press, 1989:219.
[88] Meshnick S R, Thomas A, Ranz A, et al. Artemisinin (qinghaosu): the role of intracellular hemin in its mechanism of antimalarial action[J]. Mol Biochem Parasitol, 1991,49(2): 181-189.
[89] Zhang F, Gosser DKJr, Meshnick SR. Hemin-catalyzed decomposition of artemisinin (qinghaosu)[J]. Biochem Pharmacol, 1992, 43(8):1805-1809.
[90] Krungkrai SR, Yuthavong Y. The Antimalarial Action on Plasmodium falciparum of qinghaosu and artesunate in combination with agents which modulate oxidant stress[J]. Trans R Soc Trop Med Hyg, 1987, 81(5): 710-714.
[91] Meshnick SR, Yang YZ, Lima V, et al. Iron-dependent free radical generation from the antimalarial agent artemisinin (qinghaosu)[J]. Antimicrob Agents Chemother, 1993,37(5): 1108-1114.
[92] Levander OA, Ager ALJr, Morris VC, et al. Qinghaosu, dietary vitamin E,selenium, and cod-liver oil: effect on the susceptibility of mice to the malarial parasite Plasmodium yoelii[J]. Am J Clin Nutr, 1989, 50[2]:346-352.
[93] Wu WM, Yao ZJ, Wu YL, et al. Ferrous ion induced cleavage of the peroxy bond in qinghaosu and its derivatives and the DNA damage associated with this process[J]. Chem Commun(Cambridge), 1996,18: 2213-2214.
[94] Posner GH, Oh CH. A regiospecifically oxygen-18 labeled 1, 2, 4-trioxane: a simple chemical model system to probe the mechanism(s) for the antimalarial activity of artemisinin (qinghaosu)[J]. J Am Chem Soc, 1992, 114(21):8328-8329.
[95] Jefford CW, Favarger F, Vicente MGH, et al. The decomposition of cis-fused cyclopenteno-1, 2, 4-trioxanes induced by ferrous salts and some oxophilic reagents [J]. Helv Chim Acta, 1995, 78(2): 452-458.
[96] Jefford CW, Vicente MGH, Jacquier Y, et al. The deoxygenation and isomerization of artemisinin and artemether and their relevance to antimalarial action[J]. Helv Chim Acta, 1996, 79(5): 1475-1487.
[97] Posner GH, Oh CH, Wang D, et al. Mechanism-based design, synthesis, and in-vitro antimalarial testing of new 4-methylated trioxanes structurally related to artemisinin. The importance of a carbon-centered radical for antimalarial activity[J]. J Med Chem, 1994, 37(9):1256-1258.
[98] Wang DY, Wu YL, Wu Y, et al. Further evidence for the participation of primary carbon-centered free radicals in the antimalarial action of the qinghaosu (artemisinin) series of compounds[J]. J Chem Soc [Perkin 1], 2001, 6: 605-609.
[99] Wu WM, Wu YK, Wu YL, et al. Unified mechanistic framework for the Fe(II)-induced cleavage of qinghaosu and derivatives/analogues. The first spin trapping evidence for the previous postulated secondary C-4 radical[J]. J Am Chem Soc, 1998, 120(14): 3316-3325.
[100] O'Neill PM, Bishop LP, Searle NL, et al. Biomimetic Fe(II)-mediated degradation of arteflene (Ro-42-1611).The first EPR spin-trapping evidence for the previously postulated secondary carbon-centred cyclohexyl radical[J]. J Org Chem, 2000, 65(5): 1578-1582.
[101] Butler AR, Gilbert BC, Hulme P, et al. EPR evidence for the involvement of free radicals in the iron-catalysed decomposition of qinghaosu (artemisinin) and some derivatives; antimalarial action of some polycyclic endoperoxides[J]. Free Radical Research, 1998, 28(5): 471-476.
[102] Gu JD, Chen KX, Jiang HL, et al. The Radical transformation in artemisinin: A DFT Study[J]. Journal of Physical Chemistry A, 1999, 103(46): 9364-9369.
[103] Wu Yk, Yue ZY, Wu YL. Interaction of qinghaosu ( artemisinin) with cysteine sulfhydryl mediated by traces of non-heme iron[J]. Angew Chem Int Ed Engl,1999, 38(17): 2580-2582.
[104] Wu Yk, Yue ZY, Liu HH. New insights into the degradation or qinghaosu (artemisinin) mediated by non-heme-iron chelates, and their relevance to the antimalarial mechanism[J]. Helv Chim Acta, 2001, 84(4): 928-932.
[105] Stocks PA, Bray PG, Barton VE, et al. Evidence for a common non-heme chelatable-iron-dependent activation mechanism for semisynthetic and synthetic endoperoxide antimalarial drugs[J]. Angew Chem Int Ed Engl, 2007,46(33):6278-6283.
[106] Haynes RK, Vonwiller SC. The behaviour of qinghaosu (artemisinin) in the presence of non-heme iron(II) and (III) [J]. Tetrahedron Lett, 1996, 37(2): 257-260.
[107] Avery MA, Fan P, Karle JM, et al. Structure-activity relationships of the antimalarial agent artemisinin. 3. Total synthesis of (+)-13-Carbaartemisinin and related tetra- and tricyclic Structures[J]. J Med Chem, 1996, 39(9):1885-1897.
[108] Haynes RK, Ho WY, Chan HW, et al. Highly antimalaria-active artemisinin derivatives: biological activity does not correlate with chemical reactivity[J].Angew Chem Int Ed Engl, 2004,43(11):1381-1385.
[109] Posner GH, Cumming JN, Ploypradith P, et al. Evidence for Fe(IV) = O in the molecular mechanism of action of the trioxane antimalarial artemisinin[J]. J Am Chem Soc, 1995, 117(22): 5885-5886.
[110] Traylor TG, Miksztal AR. Mechanism of hemin-catalyzed epoxidations: electron transfer from alkenes[J]. J Am Chem Soc, 1987,109(9): 2770-2774.
[111] Barton DHR, Martell AE, Sawyer DT. Dioxygen and homogeneous catalytic oxidation[M]. New York: Plenum Press, 1993:183.
[112] Posner GH, Park BS, Gonza'lez L, et al. Evidence for the importance of high-valent Fe=O and of a diketone in the molecular mechanism of action of antimalarial trioxane analogs of artemisinin[J]. J Am Chem Soc, 1996, 118(14):3537-3538.
[113] Kapetanaki S, Varotsis C. Ferryl-oxo heme intermediate in the antimalarial mode of action of artemisinin[J]. FEBS Lett, 2000,474(2-3): 238-241.
[114] Kapetanaki S, Varotsis C. Fourier transform infrared investigation of non-heme Fe(III) and Fe(II) decomposition of artemisinin and of a simplified trioxane alcohol[J]. J Med Chem, 2001,44(19): 3150-3156.
[115] Hufford CD, Lee I, ElSohly HN, et al. Structure elucidation and thermospray high-performance liquid chromatography/mass spectrscopy (HPLC/MS) of the microbial and mammalian metabolites of the antimalarial arteether[J]. Pharm Res, 1990, 7(9): 923-927.
[116] Haynes RK, Pai HH, Voerste A. Ring opening of artemisinin (Qinghaosu) and dihydroartemisinin and interception of the open hydroperoxides with formation of N-Oxidess.A chemical model for antimalarial mode of action[J]. Tetrahedron Lett, 1999,40(25): 4715-4718.
[117] Haynes RK, Vonwiller SC. The Behaviour of Qinghaosu(Artemisinin) in the Presence of Heme Iron(II) and (III) [J].Tetrahedron Lett, 1996, 37(2): 253-256.
[118] Szpilman AM, Korshin EE, Hoos R, et al. Iron(II)-Induced Degradation of Antimalariaip-Sulfonyl Endoperoxides. Evidence for the Generation of Potentially Cytotoxic Carbocations[J]. J Org Chem, 2001, 66(20):6531-6540.
[119] Robert A, Dechy-Cabaret O, Cazelles J ,et al. From mechanistic studies on artemisinin derivatives to new modular antimalarial drugs[J]. Acc Chem Res,2002, 35(3):167-174.
[120] Drew MGB, Metcalfe J, Dascombe MJ, et al. Reactions of artemisinin and arteether with acid: Implications for stability and mode of antimalarial action[J].J Med Chem, 2006,49(20):6065-6073.
[121] Ellis DS, Li ZL, Gu HM, et al. The chemotherapy of rodent malaria. XXXIX.Ultrastructural changes following treatment with artemisinine of Plasmodium berghei infection in mice, with observations of the localization of [~3H]-dihydroartemisinine in P. falciparum in vitro[J]. Ann Trop Med Parasitol,1985, 79(4):367-374.
[122] Maeno Y, Toyoshima T, Fujioka H, et al. Morphologic effects of artemisinin in Plasmodium falciparum[J]. Am J Trop Med Hyg, 1993,49(4): 485-491.
[123] Scott MD, Meshnick SR, Williams RA, et al. Qinghaosu-mediated oxidation in normal and abnormal erythrocytes[J]. J Lab Clin Med, 1989, 114(4):401-406.
[124] Meshnick SR, Tsang TW, Lin FB, et al. Activated oxygen mediates the antimalarial activity of qinghaosu[J]. Prog Clin Biol Res, 1989, 313: 95-104.
[125] Wei NM, Sadrzadeh HSM. Enhancement of hemin-induced membrane damage by artemisinin[J]. Biochem Pharmacol, 1994,48(4): 737-741.
[126] Kawai S, Kano S, Suzuki M. Morphologic effects of artemether on Plasmodium falciparum in Aotus trivirgatus[J]. Am J Trop Med Hyg, 1993, 49(6): 812-818.
[127] Jiang JB, Jacobs G, Liang DS, et al. Qinghaosu-induced changes in the morphology of Plasmodium. falciparum[J]. Am J Trop Med Hyg, 1985,34(3):424- 428.
[128] Ittarat I, Asawamahasakda W, Meshnick SR, et al. The effects of antimalarials on the Plasmodium falciparum dihydroorotate dehydrogenase[J]. Exp Parasitol,1994, 79(1):50-56.
[129] Li W, Mo WK, Shen D, et al. Yeast model uncovers dual roles of mitochondria in the action of artemisinin[J]. PLoS Genet, 2005, 1(3):329-334.
[130] Robert A, Coppel Y, Meunier B. Interaction of artemisinin(Qinghaosu) with the tetraphenylporphyrinato manganese(II) complex[J]. C R Acad Sci Ser IIb: Mec,Phys, Chim, Astron, 1997, 324(1): 59-66.
[131] Robert A, Coppel Y, Meunier B. Alkylation of heme by the antimalarial drug artemisinin[J]. Chem Commun(Cambridge), 2002, (5):414-415.
[132] Hong YL, Yang YZ, Meshnick SR. The interaction of artemisinin with malarial hemozoin[J]. Mol Biochem Parasitol, 1994,63(1):121-128.
[133] Robert A, Meunier B. Is alkylation the main mechanism of action of the antimalarial drug artemisinin?[J] Chem Soc Rev, 1998,27(4):273-279.
[134] Robert A, Meunier B. Alkylating properties of antimalarial artemisinin derivatives and synthetic trioxanes when activated by a reduced heme model[J].Chem-EurJ, 1998, 4(7):1287-1296.
[135] Robert A, Cazelles J, Meunier B. Characterization of the alkylation product of heme by the drug artemisinin[J]. Angew Chem Int Ed Engl, 2001,40(10):1954-1957.
[136] Robert A, Benoit-Vical F, Claparols C, et al. The antimalarial drug artemisinin alkylates heme in infected mice[J]. Proc Natl Acad Sci U S A, 2005, 102(38): 13676-13680.
[137] Benoit-Vical F, Robert A, Meunier B. In vitro and in vivo potentiation of artemisinin and synthetic endoperoxide antimalarial drugs by metalloporphyrins[J]. Antimicrob Agents Chemother, 2000, 44(10):2836-2841.
[138] Cazelles J, Robert A, Meunier B. Alkylating capacity and reaction products of antimalarial trioxanes after activation by a heme model[J]. J Org Chem, 2002,67(3):609-619.
[139] Cazelles J, Camuzat-Dedenis B, Provot O, et al. Alkylating properties of synthetic trioxanes related to artemisinin[J]. J Chem Soc [Perkin 1],1(8):1265-1270.
[140] Provot O, Camuzat-Dedenis B, Hamzaoui M, et al. Structure-activity relationships of synthetic tricyclic trioxanes related to artemisinin: the unexpected alkylative property of a 3-(methoxymethy) analog[J]. European J OrgChem, 1999, 8, 1935-1938.
[141] Sumpan P, Bongkoch T,Yodhathai T, et al.Correlation of antimalarial activity of artemisinin derivatives with binding affinity with ferroprotoporphyrin IX[J]. J Med Chem, 1997, 40(5):633-638.
[142] Robert A, Benoit-Vical F, Dechy-Cabaret O, et al. From classical antimalarial drugs to new compounds based on the mechanism of action of artemisinin[J].Pure Appl Chem, 2001, 73(7):1173-1188.
[143] Slater AFG, Cerami A. Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites[J]. Nature, 1992, 355(6356): 167-169.
[144] Slater AFG, Swiggard WJ, Orton BR, et al. An iron-carboxylate bond links the heme units of malaria pigment [J], Proc Natl Acad Sci U S A, 1991,88(2):325-329.
[145] Pandey AV, Tekwani BL, Singh RL, et al. Artemisinin, an endoperoxide antimalarial, disrupts the hemoglobin catabolism and heme detoxification systems in malarial parasite[J]. J Biol Chem, 1999, 274(27):19383-19388.
[146] Kannan R, Kumar K, Sahal D, et al. Reaction of artemisinin with hemoglobin: Implications for antimalarial activity[J]. Biochemical Journal, 2005,385(2):409-418.
[147] Kannan R, Sahal D, Chauhan VS. Heme-artemisinin adducts are crucial mediators of the ability of artemisinin to inhibit heme polymerization[J]. Chem Biol, 2002,9(3):321-332.
[148] Bray PG, Ward SA, O'Neill PM. Quinolines and artemisinin: chemistry, biology and history[J]. Curr Top Microbiol Immunol, 2005, 295: 3-38.
[149] Stahel E, Druilhe P, Gentilini M. Antagonism of chloroquine with other antimalarials[J]. Trans R Soc Trop Med Hyg, 1988, 82(2):221.
[150] Haynes RK, Monti D, Taramelli D. Artemisinin antimalarials do not inhibit hemozoin formation[J]. Antimicrob Agents Chemother, 2003, 47(3): 1175.
[151] Asawamahasakda W, Ittarat I, Chang CC, et al. Effects of antimalarials and protease inhibitors on plasmodial hemozoin production[J]. Mol Biochem Parasitol, 1994, 67(2):183-191.
[152] Cazelles J, Robert A, Meunier B. Characterization of the main radical and products resulting from a reductive activation of the antimalarial Arteflene (Ro-42-1611)[J]. J Org Chem, 1999, 64(18): 6776-6781.
[153] O'Neill PM, Bishop LP, Searle NL, et al. The biomimetic iron-mediated degradation of Arteflene (Ro-42-1611), an endoperoxide antimalarial:Implications for the mechanism of antimalarial activity[J]. Tetrahedron Lett,1997, 38(24):4263-4266.
[154] Eckstein-Ludwig U, Webb RJ, van Goethem IDA, et al. Artemisinins target the SERCA of Plasmodiumfalcipamm[J]. Nature, 2003, 424(6951): 957-961.
[155] Parapini S, Basilico N, Mondani M, et al. Evidence that haem iron in the malaria parasite is not needed for the antimalarial effects of artemisinin[J]. FEBS Lett, 2004, 575(1-3):91-94.
[156] Atkins PW. Physical Chemistry[M]. Oxford: Oxford University Press, 1994:846-856.
[157] Atamna H, Ginsburg H. The malaria parasite supplies glutathione to its host cell Investigation of glutathione transport and metabolism in human erythrocytes infected with Plasmodiumfalciparum[J]. Eur J Biochem, 1997, 250(3):670-679.
[158] Linares GE, Rodriguez JB. Current status and progresses made in malaria chemotherapy[J]. Curr Med Chem, 2007,14(3):289-314.
[159] Ginsburg H, Famin O, Zhang J, Krugliak M. Inhibition of glutathione-dependent degradation of heme by chloroquine and amodiaquine as a possible basis for their antimalarial mode of action[J]. Biochem Pharmacol, 1998, 56(10):1305-1313.
[160] Famin O, Krugliak M, Ginsburg H. Kinetics of inhibition of glutathione-mediated degradation of Ferriprotoporphyrin IX by antimalarial drugs[J]. Biochem Pharmacol, 1999, 58(1): 59-68.
[161] Wang DY, Wu YL. A possible antimalarial action mode of qinghaosu (artemisinin) series compounds. Alkylation of reduced glutathione by C-centered primary radicals produced from antimalarial compound qinghaosu and 12- (2,4-dimethoxyphenyl)-12-deoxoqinghaosu[J]. Chem Commun(Camb),2000,22:2193-2194.
[162] Wu YL, Chen HB, Jiang K, et al. Interaction of biomolecules with qinghaosu (artemisinin) and its derivatives in the presence of ferrous ion-an exploration of antimalarial mechanism[J]. Pure Appl Chem, 1999, 71(6): 1139-1142.
[163] Aboul-Enein HY. Evidence that the antimalarial activity of artemisinin is not mediated via intercalation with nucleotides[J]. Drug Des Deliv, 1989, 4(2):129-133.
[164] Yang YZ, Asawamahasakda W, Meshnick SR. Alkylation of human albumin by the antimalarial artemisinin[J]. Biochem Pharmacol, 1993,46(2): 336-339.
[165] Yang YZ, Little B, Meshnick SR. Alkylation of proteins by artemisinin effects of heme, pH, and drug structure[J]. Biochem Pharmacol, 1994, 48(3):569-573.
[166] Asawamahasakda W, Benakis A, Meshnick SR. The interaction of artemisinin with red cell membranes[J]. J Lab Clin Med, 1994, 123:757-762.
[167] Uhlemann AC, Wittlin S, Matile H, et al. Mechanism of antimalarial action of the synthetic trioxolane RBX11160 (OZ277) [J]. Antimicrob Agents Chemother,2007, 51(2): 667-672.
[168] Uhlemann AC, Cameron A, Eckstein-Ludwig U, et al. A single amino acid residue can determine the sensitivity of SERCAs to artemisinins[J]. Nat Struct Mol Biol,2005,12(7): 628-629.
[169] Jambou R, Legrand E, Niang M, et al. Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6[J]. Lancet, 2005, 366(9501):1960-1963.
[170] Bhisutthibhan J, Pan XQ, Hossler PA, et al. The Plasmodium falciparum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisinin[J]. J Biol Chem, 1998,273 (26):16192-16198.
[171] Raphael P, Takakuwa Y, Manno S, et al. The Plasmodium falciparum translationally controlled tumor protein: subcellular localization and calcium binding[J]. Eur J Cell Biol, 1999, 78 (9):665-670.
[172] Raphael P, Takakuwa Y, Manno S, et al. A cysteine protease activity from Plasmodium falciparum cleaves human erythrocyte ankyrin[J]. Mol Biochem Parasitol, 2000, 110(2): 259-272.
[173] Rosenthal PJ, Sijwali PS, Singh A, et al. Cysteine proteases of malaria parasites:Targets for Chemotherapy[J]. Curr Pharm Des, 2002, 8(18):1659-1672.
[174] Rosenthal PJ. Plasmodium falciparum effects of proteinase inhibitors on globin hydrolysis by cultured malaria parasites[J]. Exp Parasitol, 1995, 80(2): 272-281.
[175] Shenai BR, Sijwali PS, Singh A, et al. Characterization of native and recombinant Falcipain-2, a principal trophozoite cysteine protease and essential hemoglobinase of Plasmodium falciparum[J]. J Biol Chem, 2000, 275(37):29000-29010.
[176] Sijwali PS, Rosenthal PJ. Gene disruption confirms a critical role for the cysteine protease Falcipain-2 in hemoglobin hydrolysis by Plasmodium falciparum[J]. Proc Natl Acad Sci U S A, 2004,101(13): 4384-4389.
[177] Sullivan DJJr, Gluzman IY, Goldberg DE. Plasmodium hemozoin formation mediated by histidine-richproteins[J]. Science, 1996, 271(5246): 219-222.
[178] Choi CY, Cerda JF, Chu HA, et al. Spectroscopic characterization of the heme-binding sites in Plasmodium falciparum histidine-rich protein 2[J].Biochemistry, 1999, 38(51):16916-16924.
[179] Robert A, Benoit-Vical F, Meunier B. The key role of heme to trigger the antimalarial activity oftrioxanes[J].Coord Chem Rev,2005,249(17-18):1927-1936.
[180]徐筱杰,侯廷军,乔学斌等.计算机辅助药物分子设计[M].北京:化学工业出版社,2004:325.
[181]陈健全,迟翰林.药物分子与其受体的快速对接方法研究[J].科学通报,1996,44(11):1161-1165.
[182]李纯莲,王希诚,赵金城.药物分子对接中的构象搜索策略[J].计算机与应用化学,2004,21(2):201-205
[183]Kitchen DB,Decomez H,Furr JR,et al.Docking and scoring in virtual screening for drug discovery:methods and applications[J].Nat Rev Drug Discov,2004,3(11):935-949.
[184]Muegge I,Martin YC.A general and fast scoring function for protein-ligand interactions:A simplified approach[J].J Med Chem,1999,42(5):791-804.
[185]Gohlke H,Hendlich M,Klebe G.Knowledge-based scoring function to predict protein-ligandi nteractions[J].J Mol Biol,2000,295(2):337-356.
[186]Jiang F,Kim SH."Soft docking":matching of molecular surface cubes[J].J Mol Biol,1991,219(1):79-102.
[187]Kuntz ID.Structure-based strategies for drug design and discovery[J].Science,1992,257(5073):1078-1082.
[188]Goodsell DS,Olsen AJ.Automated docking of substrates to proteins by simulated annealing[J].Proteins,1990,8(3):195-202.
[189]Affinity user guide.MSI Inc.San Diego,USA,2002.
[190]Morris GM,Goodsell DS,Halliday RS,et al.Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function[J].J Comput Chem,1998,19(14):1639-1662.
[191]Kuntz ID,Blaney JM,Oatley SJ,et al.A geometric approach to macromolecule-ligand interactions[J].J Mol Biol,1982,161(2):269-288.
[192]Rarey M,Kramer B,Lengauer T,et al.A fast flexible docking method using an incremental construction algorithm[J].J Mol Biol,1996,261(3):470-489.
[193]徐昕,王南钦,吕鑫等.量子化学的研究现状、发展趋势与展望[J].化学进展,1996,8(1):30-42.
[194]Friesner RA.Ab initio quantum chemistry:Methodology and applications[J].Proc Natl Acad Sci U S A,2005,102(19):6648-6653.
[195]Hatree DR.The calculations of atomic structure[M].New York:John Wiley & Sons.1957:10.
[196]笪良国,张倩茹.量子化学计算方法及其在结构化学中的应用[J].淮南师范学院学报,2007,9(3):101-103.
[197]Dewar MJS.The semiempirical approach to chemistry[J].Int J Quantum Chem,1992,44(4):427-447.
[198]Hohenberg P,Kohn W.Inhomogeneous electron gas[J].Phys Rev B,1964,136(3B):864-871.
[199]Thomas LH.The calculation of atomic fields[J].Proc Camb Philol Soc,1927,23:542-548.
[200]Fermi E.Eine statistische methode zur bestimmung einiger eigenschaften des atoms und ihre anwendung auf die theories des periodischen systems der elemente[J].Zeits f.Physik,1928,48(1-2):73-79.
[201]Kohn W,Sham LJ.Self-Consistent Equations Including Exchange and Correlation Effects[J].Phys Rev A,1965,140(4A):1133-1138.
[202]黄美纯.密度泛函理论的若干进展[J].物理学进展,2000,9(3):199-219.
[203]Collins JB,Schleyer PVR,Binkley JS,et al.Self-consistent molecular orbital methods.ⅩⅦ.Geometries and binding energies of second-row molecules.A comparison of three basis sets[J].J Chem Phys,1976,64(12):5142-5151.
[204]Hariharan PC,Pople JA.The influence of polarization functions on molecular orbital hydrogenation energies[J].Theor Chim Acta,1973,28:213-222.
[205]Andzelm J,Wimmer E.Density functional Gaussian-type-orbital approach to molecular geometries,vibrations,and reaction energies[J].J Chem Phys,1992,96(2):1280-1303.
[206]Scuseria GE.Comparison of coupled-cluster results with a hybrid of Hartree-Fock and density functional theory[J].J Chem Phys,1992,95(10):7528-7530.
[207]Hehre WJ,Ditchfield R,Pople JA.Self-consistent molecular orbital methods.Ⅻ.Further extensions of Gaussian-Type basis sets for use in molecular orbital studies of organic molecules[J].J Chem Phys,1972,56(5):2257-2261.
[208]Ditchfield R,Hehre WJ,Pople JA.Self-consistent molecular orbital methods.Ⅸ.An extended Gaussian-Type basis for molecular-orbital studies of organic molecules[J].J Chem Phys,1971,54(2):724-728.
[209]Clark T,Chandrasekhar J,Spitznagel GW,et al.Efficient diffuse function-augmented basis sets for anion calculations.Ⅲ.The 3-21+G basis set for first-row elements,Li-F[J].J Comput Chem,1983,4(3):294-301.
[210]Frisch MJ,Trucks G.W,Schlegel HB,et al.Gaussian 03,Revision B.03;Gaussian Inc.,Pittsburgh,PA,2003.
[211]赵国屏等.生物信息学[M].北京:科学出版社,2004:149.
[212]Anfinsen CB.Principles that govern the folding of protein chains[J].Science,1973,181(96):223-230.
[213]Sternberg MJE,Bates PA,Kelly LA,et al.Progress in protein structure prediction:assessment of CASP3[J].Curr Opin Struct Biol,1999,9(3):368-373.
[214]Philipe B,Helgew W.Structural Bioinformatics[M].New York:John Wiley &Sons Inc,2003:509-512.
[215]Orengo CA,Jones DT,Thornton JM.Protein superfamilies and domain superfolds[J].Nature,1994,372(6507):631-634.
[216]Finkelstein AV,Ptitsyn OB.Why do globular proteins fit the limited set of folding patterns[J].Prog Biophys Mol Biol,1987,50(3):171-190.
[217]RCSB Protein Data Bank.An information portal to biological macromolecular structures[EB/OL].:http://www.rcsb.org/pdb/statistics/contentGrowthChart.do?c ontent=fold-scop,2008-10-07.
[218]蒋彦,王小行,曹毅等.基础生物信息学及应用[M].北京:清华大学出版社,2003:177.
[219]Gardner MJ,Hall N,Fung E,et al.Genome sequence of the human malaria parasite Plasmodiumfalciparum[J].Nature,2002,419(6906):498-511.
[220]Meshnick SR.Artemisinin:mechanisms of action,resistance and toxicity[J].Int J Parasitol,2002,32(12):1655-1660.
[221]Altschul SF,Madden TL,Schaffer AA,et al.Gapped BLAST and PSI-BLAST:a new generation of protein database searchprograms[J].Nucleic Acids Res,1997,25(17):3389-3402.
[222]Braun W,GO N.Calculation of protein conformations by proton-proton distance constraints:A new efficient algorithm[J].J Mol Biol,1985,186(3):611-626.
[223]Krogh A,Brown M,Mian IS,et al.Hidden Markov models in computational biology.Applications to protein modeling[J].J Mol Biol,1994,235(5):1501-1531.
[224]Jung M,Kim H,Nam KY,et al.Three-dimensional structure of Plasmodium falciparum Ca2+-ATPase(PfATP6) and docking of artemisinin derivatives to PfATP6[J].Bioorg Med Chem Letters,2005,15(12):2994-2997.
[225]Sali A,Blundell TL.Comparative protein modelling by satisfaction of spatial restraints[J].J Mol Biol,1993,234(3):779-815.
[226]Toyoshima C,Nomura H,Tsuda T.Lumenal gating mechanism revealed in calcium pump crystal structures with phosphate analogues[J].Nature,2004,432(7015):361-368.
[227]Morris AL,MacArthur MW,Hutchinson EG,et al.Stereochemical quality of protein structure coordinates[J].Proteins,1992,12(4):345-364.
[228]L(u|¨)thy R,Bowie JU,Eisenberg D.Assessment of protein models with three-dimensional profiles[J].Nature,1992,356(6364):83-85.
[229]Colovos C,Yeates TO.Verification of protein structures:patterns ofnonbonded atomic interactions[J].Protein Sci,1993,2(9):1511-1519.
[230]Hooft RWW,Vriend G,Sander C,et al.Errors in protein structures[J].Nature,1996,381(6580):272.
[231]Sanchez JC,Schaller D,Ravier F,et al.Translationally controlled tumor protein:a protein identified in several nontumoral cells including erythrocytes[J].Electrophoresis,1997,18(1):150-155.
[232]傅作申,陈知航,张娟等.恶性疟原虫海南株翻译控制肿瘤蛋白(TCTP)基因在M15中的表达[A].2006中国科协年会论文集[C].北京:中国科学技术协会学会学术部,2006:78-81.
[233]Pontius J,Richelle J,Wodak SJ.Deviations from standard atomic volumes as a quality measure for protein crystal structures[J].J Mol Biol,1996,264(1):121-136.
[234]Lisgarten JN,Potter BS,Bantuzeko C,et al.Structure,absolute configuration,and conformation of the antimalarial compound,Artemisinin[J].J Chem Crystallogr,1998,28(7):539-543.
[235]Sijwali PS,Kato K,Seydel KB,et al.Plasmodiumfalciparurn cysteine protease falcipain-1 is not essential in erythrocytic stage malaria parasites[J].Proc Natl Acad Sci U S A,2004,101(23):8721-8726.
[236]Jeong JJ,Kumar A,Hanada T,et al.Cloning and characterization of Plasmodium falciparum cysteine protease,falcipain-2B[J].Blood Cells Mol Dis,2006,36(3):429-435.
[237]Sijwali PS,Koo J,Singh N,et al.Gene disruptions demonstrate independent roles for the four falcipain cysteine proteases of Plasmodium falciparum[J].Mol Biochem Parasitol, 2006,150(1):96-106.
[238] Hogg T, Nagarajan K, Herzberg S, et al. Structural and functional characterization of Falcipain-2, a hemoglobinase from the malarial parasite Plasmodiumfalciparum[J]. J Biol Chem, 2006, 281(35):25425-25437.
[239] Het(?)nyi C, van der Spoel D. Efficient docking of peptides to proteins without prior knowledge of the binding site[J]. Protein Sci, 2002, 11 (7): 1729-1737.
[240] Jining L, Makagiansar I, Yusuf-Makagiansar H, et al. Design, structure and biological activity of beta-turn peptides of CD2 protein for inhibition of T-cell adhesion[J]. Eur J Biochem, 2004, 271(14):2873-2886.
[241] Espinoza-Fonseca LM. Targeting MDM2 by the small molecule RITA: towards the development of new multi-target drugs against cancer[J]. Theor Biol Med Model, 2005, 2:38.
[242] Sunaga S, Yoshimori A, Shiokawa D, et al. Structure basis for the inhibitory mechanism of a novel DNase gamma-specific inhibitor, DR396[J]. Bioorg Med Chem, 2006,14(12):4217-4226.
[243] Street IP, Armstrong CR, Withers SG Hydrogen bonding and specificity. Fluorodeoxy sugars as probes of hydrogen bonding in the glycogen phosphorylase-glucose complex[J]. Biochemistry, 1986, 25(20):6021-6027.
[244] Fersht AR. Basis of biological specificity[J]. Trends Biochem Sci, 1984,9(4): 145-147.
[245] Fersht AR, Shi JP, Knill-Jones J, et al. Hydrogen bonding and biological specificity analysed by protein engineering[J]. Nature, 1985,314(6008):235-238.
[246] Goh LL, Sim TS. Homology modeling and mutagenesis analyses of Plasmodiumfalciparum falcipain 2A: implications for rational drug design[J].Biochem Biophys Res Commun, 2004, 323(2):565-572.
[247] Berger A, Schechter I. Mapping the active site of papain with the aid of peptide substrates and inhibitors[J]. Philos Trans R Soc Lond B Biol Sci, 1970,257(813):249-264.
[248] Sabnis YA, Desai PV, Rosenthal PJ, et al. Probing the structure of falcipain-3, a cysteine protease from Plasmodiumfalciparum: comparative protein modeling and docking studies[J]. Protein Sci, 2003, 12(3):501-509.
[249] Yamamoto D, Matsumoto K, Ishida T, et al. Crystal structure and molecular conformation of E-64, a cysteine protease inhibitor[J]. Chem Pharm Bull, 1989, 37(10):2577-2581.
[250]Matsumoto K,Mizoue K,Kitamura K,et al.Structural basis of inhibition of cysteine proteases by E-64 and its derivatives[J].Biopolymers,1999,51(1):99-107.
[251]Singh A,Walker KJ,Sijwali PS,et al.A chimeric cysteine protease of Plasmodium berghei engineered to resemble the Plasrnodium falciparum protease falcipain-2[J].Protein Eng Des Sel,2007,20(4):171-177.
[252]Avery MA,Alvim-Gaston M,Rodrigues CR,et al.Structure-activity relationships of the antimalarial agent artemisinin.6.The development of predictive in vitro potency models using CoMFA and HQSAR methodologies[J].J Med Chem,2002,45(2):292-303.
[253]Lin AJ,Klayman DL,Milhous WK.Antimalarial activity of new water-soluble dihydroartemisinin derivatives[J].J Med Chem,1987,30(11):2147-2150.
[254]Avery MA,Bonk JD,Chong WK,et al.Structure-activity relationships of the antimalarial agent artemisinin.2.Effect ofheteroatom substitution at O-11:synthesis and bioassay ofN-alkyl-11-aza-9-desmethylartemisinins[J].J Med Chem,1995,38(26):5038-5044.
[255]Posner GH,Oh CH,Gerena L,et al.Synthesis and antimalarial activities of structurally simplified 1,2,4-trioxanes related to artemisinin[J].Heteroat Chem,1995,6(2):105-116.
[256]Guha R,Jurs PC.Development of QSAR models to predict and interpret the biological activity of artemisinin analogues[J].J Chem Inf Comput Sci,2004,44(4):1440-1449.
[257]Vennerstroml LJ,Arbe-Barnes S,Brun R,et al.Identification of an antimalarial synthetic trioxolane drug development candidate[J].Nature,2004,430:900-904.
[258]Rogers D,Hopfinger AJ.Application of Genetic Function Approximation to Quantitative Structure-Activity Relationships and Quantitative Structure-Property Relationships[J].J Chem Inf Comput Sci,1994,34(4):854-866.
[259]朱杰,季海涛,张万年.进化算法在定量构效关系研究中的应用[J].中国药物化学杂志,1999,9(2):151-156.
[260]Bhisutthibhan J,Meshnick SR.Immunoprecipitation of[~3H]dihy-droartemisinin translationally controlled tumor protein(TCTP) adduct from Plasmodium falciparum infected erythrocytes by using anti-TCTP antibodies[J].Antimicrob Agents Chemother, 2001, 45(8):2397-2399.
[261] Walker DJ, Pitsch J, Peng MM. Mechanisms of artemisinin resistance in the rodent malaria pathogen[J]. Antimicrob Agents Chemother, 2000, 44(2):344-347.
[262] Bommer UA, Thiele BJ. The translation controlled protein (TCTP)[J]. Int J Biochem Cell Biol, 2004, 36:379-385.
[263] MacDonald SM, Rafnar T, Langdon J, et al. Molecular dentification of an IgE-dependenthistamine-releasing factor[J]. Science, 1995, 269: 688-690.
[264]Wellems TE, Howard RJ. Homologous genes encode two distinct histidine-rich proteins in a cloned isolate of Plasmodium falciparum[J]. Proc Natl Acad Sci U S A, 1986, 83(16):6065-6069.
[265] Panton LJ, McPhie P, Maloy WL, et al. Purification and partial characterization of an unusual protein of Plasmodium falciparum: histidine-rich protein II[J].Mol Biochem Parasitol, 1989, 35(2):149-160.
[266] Goh LL, Sim TS. Characterization of amino acid variation at strategic positions in parasite and human proteases for selective inhibition of falcipains in Plasmodium falciparum[J]. Biochem Biophys Res Commun, 2005,335(3):762-770.
[267] Jeong JJ, Kumar A, Hanada T, et al. Cloning and characterization of Plasmodium falciparum cysteine protease, falcipain-2B[J]. Blood Cells Mol Dis,2006, 36(3):429-435.
[268] Dahl EL, Rosenthal PJ. Biosynthesis, localization, and processing of falcipain cysteine proteases of Plasmodium falciparum[J]. Mol Biochem Parasitol, 2005,139 (2):205-212.
[269] Singh N, Sijwali PS, Pandey KC, et al. Plasmodium falciparum: biochemical characterization of the cysteine protease falcipain-2'[J]. Exp Parasitol, 2006,112(3):187-192.
[270] Eksi S, Czesny B, van Gemert GJ, et al. Inhibition of Plasmodium falciparum oocyst production by membrane-permeant cysteine protease inhibitor E64d[J].Antimicrob Agents Chemother, 2007, 51(3):1064-1070.
[271] Guruprasad K, Reddy BV, Pandit MW. Correlation between stability of a protein and its dipeptide composition: a novel approach for predicting in vivo stability of a protein from its primary sequence[J]. Protein Eng, 1990,4(2):155-161.
[272]Kyte J,Doolittle RF.A simple method for displaying the hydropathic character of a protein[J].J Mol Biol,1982,157(1):105-132.
[273]Muskal S M,Holbrook R S,Kim S H.Prediction of the disulfide bonding state of cysteine in proteins[J].Protein Eng(S0269-2139),1990,3:667-672.
[274]Fariselli P,Riccobelli P,Casadio R.Role of evolutionary information in predicting the disulfide-bonding state of cysteine in proteins[J].Proteins (S0887-3585),1999,36:340-346.
[275]Ferre F,Clote P.DiANNA:a web server for disulfide connectivity prediction[J].Nucleic Acids Res,2005,(Web Server issue):W230-232.
[276]Kerr ID,Lee JH,Pandey KC,et al.Structures of falcipain-2 and falcipain-3bound to small molecule inhibitors:implications for substrate specificity[J].J Med Chem,2009,52(3):852-857.
[277]Shi W,Ting LM,Kicska GA,et al.Plasmodium falciparum purine nucleoside phosphorylase:crystal structures,immucillin inhibitors,and dual catalytic function[J].J Biol Chem,2004,279(18):18103-18106.
[278]Schnick C,Robien MA,Brzozowski AM,et al.Structures of Plasmodium falciparurn purine nucleoside phosphorylase complexed with sulfate and its natural substrate inosine[J].Acta Crystallogr D Biol Crystallogr,2005,61(Pt 9):1245-1254.
[279]Robien MA,Nguyen KT,Kumar A,et al.An improved crystal form of Plasmodium falciparum peptide deformylase[J].Protein Sci,2004,13(4):1155-1163.
[280]Kumar A,Nguyen KT,Srivathsan S,et al.Crystals ofpeptide deformylase from Plasmodium falciparum reveal critical characteristics of the active site for drug design[J].Structure,2002,10(3):357-367.
[281]Caruthers J,Bosch J,Buckner F,et al.Structure ofa ribulose 5-phosphate 3-epimerase from Plasmodium falciparum[J].Proteins,2006,62(2):338-342.
[282]Tanaka N,Nakanishi M,Kusakabe Y,et al.Crystal structure of S-adenosyl-L-homocysteine hydrolase from the human malaria parasite Plasmodium falciparum[J].J Mol Biol,2004,343(4):1007-1017.
[283]Holmes MA,Buckner FS,Van Voorhis WC,et al.Structure ofribose 5-phosphate isomerase from Plasmodium falciparum[J].Acta Crystallogr Sect F Struct Biol Cryst Commun,2006,62(Pt 5):427-431.
[284]Hamada K,Ago H,Sugahara M,et al.Oxyanion hole-stabilized stereospecific isomerization in ribose-5-phosphate isomerase (Rpi)[J]. J Biol Chem, 2003,278(49):49183-49190.
[285] Bello AM, Poduch E, Liu Y, et al. Structure-activity relationships of C6-uridine derivatives targeting plasmodia orotidine monophosphate decarboxylase[J]. J Med Chem, 2008,51(3):439-448.
[286] Freundlich JS, Wang F, Tsai HC, et al. X-ray structural analysis of Plasmodium falciparum enoyl acyl carrier protein reductase as a pathway toward the optimization of triclosan antimalarial efficacy[J]. J Biol Chem, 2007,282(35):25436-25444.
[287] Dufe VT, Qiu W, Miiller IB, et al. Crystal structure of Plasmodium falciparum spermidine synthase in complex with the substrate decarboxylated S-adenosylmethionine and the potent inhibitors 4MCHA and AdoDATO[J]. J Mol Biol, 2007, 373(1): 167-177.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |