HEPT类HIV-1逆转录酶衍生物的CoMFA、CoMSIA及HQSAR分析
|
摘要
采用比较分子力场分析法(CoMFA)、比较分子相似因子分析法(CoMSIA)和分子全息定量结构关系(HQSAR)对1-[(2-羟乙氧)甲基]-6-苯硫基胸腺嘧啶(HEPT)类衍生物进行了分子活性构象选择、分子叠合、空间力场范围建立以及相应3D-QSAR模型建立。结果表明:该法所建模型对此类化合物具有良好的预测能力。CoMFA模型显示,交叉验证系数(q2)为0.565,非交互验证系数(r2)为0.892;CoMSIA模型显示,最佳q2为0.636,r2为0.953;最佳的HQSAR模型显示,q2为0.876,r2为0.929,最佳全息长度为97。根据三维等势图和HQSAR色码图设计了7个有较高活性的HEPT类化合物。
Comparative molecular field analysis(Co MFA),comparative molecular similarity indices analysis(CoMSIA) and hologram quantitative structure-activity relationship(HQSAR) for 1-[(2-hydroxyethyloxy)methyl]-6-phenylthio thymidine(HEPT) derivatives were used to have molecular active conformation selection,molecular alignment,as well as the establishment of corresponding 3 D-QSAR model.The model established by this method had a good ability to predict these compounds.For CoMFA model,the cross-validated q2 value and non-cross-validated r2 value was 0.565 and 0.892,respectively.The best q2 value for CoMSIA model was 0.636 and r2 value was 0.953.The most effective HQSAR model was obtained with q2 value of 0.876 and r2 value of 0.929,and the best hologram length value was 97.Seven highly active HEPT compounds were designed based on three-dimensional contour maps and HQSAR color code map.Observations derived from these QSAR modeling study may provide a theoretical reference for designing more active HEPT derivatives.
Comparative molecular field analysis(Co MFA),comparative molecular similarity indices analysis(CoMSIA) and hologram quantitative structure-activity relationship(HQSAR) for 1-[(2-hydroxyethyloxy)methyl]-6-phenylthio thymidine(HEPT) derivatives were used to have molecular active conformation selection,molecular alignment,as well as the establishment of corresponding 3 D-QSAR model.The model established by this method had a good ability to predict these compounds.For CoMFA model,the cross-validated q2 value and non-cross-validated r2 value was 0.565 and 0.892,respectively.The best q2 value for CoMSIA model was 0.636 and r2 value was 0.953.The most effective HQSAR model was obtained with q2 value of 0.876 and r2 value of 0.929,and the best hologram length value was 97.Seven highly active HEPT compounds were designed based on three-dimensional contour maps and HQSAR color code map.Observations derived from these QSAR modeling study may provide a theoretical reference for designing more active HEPT derivatives.
引文
[1]Wang Xiying(王喜英).Study on the dynamics of HIV epidemic models with switching parameters and pulse control[D].Xi'an:Journal of Northwestern Polytechnical University(西北工业大学),2015.
[2]Liu X,Wang H,Huwanbiao Z.Global stability of an HIVpathogenesis model with cure rate.[J].Nonlinear Analysis Real World Applications,2011,12(6):2947-2961.
[3]Meng Ge(孟歌),He Yanping(何严萍).Three dimensional quantitative structure-activity relationship of HEPT analogues as HIV-1 reverse transcriptase inhibitors[J].Chemical Jouranl of Chinese Universities(高等学校化学学报),2002,23(7):1304-1308.
[4]Meng Ge(孟歌),Chen Fener(陈芬儿).Research progress of HEPTanalogs as nonnucleoside HIV-1 reverse transcriptase inhibitors[J].Chinese Journal of Medicinal Chemistry(中国药物化学杂志),2004,14(1):56-64.
[5]Mandal A,Roy K.Predictive QSAR modeling of HIV reverse transcriptase inhibitor TIBO derivatives.[J].European Journal of Medicinal Chemistry,2009,44(4):1509-1524
[6]Lu P,Wei X R.Co MFA and CoMSIA studies on HIV-1 attachment inhibitors[J].European Journal of Medicinal Chemistry,2010,45(5):1792-1798.
[7]Heravi Y E,Sereshti H,Saboury A A,et al.3D QSAR studies,Pharmacophore modeling,and virtual screening of diarylpyrazolebenzenesulfonamide derivatives as a template to obtain new inhibitors,using human carbonic anhydraseⅡas a model protein[J].JEnzyme Inhib Med Chem,2017,32(1):688-700.
[8]Hu Songqing(胡松青),Mi Siqi(米思奇),Jia Xiaolin(贾晓林),et al.3D-QSAR study and molecular design of benzimidazole derivatives as corrosion inhibitors[J].Chemical Jouranl of Chinese Universities(高等学校化学学报),2011,32(10):2402-2409.
[9]Awasthi M,Singh S,Pandey V P,et al.CoMFA and CoMSIA-based designing of resveratrol derivatives as amyloid-beta aggregation inhibitors against alzheimer's disease[J].Medicinal Chemistry Research,2018,27(4):1-19.
[10]Magalh?es U O,Souza A M,Albuquerque M G,et al.Hologram quantitative structure-activity relationship and comparative molecular field analysis studies within a series of tricyclic phthalimide HIV-1integrase inhibitors[J].Drug Des Devel Ther,2013,7:953-961.
[11]Cheng Y,Zhou M,Tung C H,et al.Studies on two types of PTP1Binhibitors for the treatment of type 2 diabetes:Hologram QSAR for OBA and BBB analogues[J].Bioorganic&Medicinal Chemistry Letters,2010,20(11):3329-3337.
[12]Xiang Yuhong(相玉红),Xiao Aijing(肖爱婧),Zhang Zhuoyong(张卓勇).QSAR studies on a series of tetrahydroisoquinoline derivatixes by using CoMFA,CoMSIA,HQSAR[J].Journal of Lanzhou University(Natural Sciences)(兰州大学学报:自科版),2009,45(4):88-93.
[13]Noorizadeh H,Sajjadifar S,Farmany A.A quantitative structureactivity relationship study of anti-HIV activity of substituted HEPTusing nonlinear models[J].Medicinal Chemistry Research,2013,22(11):5442-5452.
[14]Tong J B,Li Y Y,Jiang G Y,et al.Application of an R-group search technique in the molecular design of dipeptidyl boronic acid proteasome inhibitors[J].Journal of the Serbian Chemical Society,2016,82:1025-1037.
[15]Shirota Y,Luo H,Qin W,et al.Hepatitis C virus(HCV)NS5A binds RNA-dependent RNA polymerase(RdRP)NS5B and modulates RNA-dependent RNA polymerase activity[J].Journal of Biological Chemistry,2002,277(13):11149-11155.
[16]Yu S,Yuan J,Shi J,et al.HQSAR and topomer CoMFA for predicting melanocortin-4 receptor binding affinities of trans-4-(4-chlorophenyl)pyrrolidine-3-carboxamides[J].Chemometrics&Intelligent Laboratory Systems,2015,146:34-41.
[17]Tenenhaus M,Vinzi V E,Chatelinc Y M,et al.PLS path modeling[J].Computational Statistics&Data Analysis,2005,48(1):159-205.
[18]Patel S,Stott IP,Bhakoo M,et al.Patenting computer-designed peptides[J].Journal of Computer-Aided Molecular Design,1998,12(6):543-556.
[19]Cherkasov A,Jankovic B.Application of'inductive'QSARdescriptors for quantification of antibacterial activity of cationic polypeptides[J].Molecules,2004,9(12):1034-1052.
[20]Fjell C D,Jenssen H,Kai H,et al.Identification of novel antibacterial peptides by chemoinformatics and machine learning[J].Journal of Medicinal Chemistry,2009,52(7):2006-2015.
[21]He Y,Yan W,Coito C,et al.The regulation of hepatitis C virus(HCV)internal ribosome-entry site-mediated translation by HCVreplicons and nonstructural proteins[J].Journal of General Virology,2003,84(3):535-543.
[22]Garcia-Saez I,Debonis S R,Trucco F,et al.Structure of human Eg5in complex with a new monastrol-based inhibitor bound in the Rconfiguration[J].Journal of Biological Chemistry,2007,282(13):9740-9747.
[23]Li M P,Zhang S W.Quantitative structure property relationship studies of the pKa values for sulfonamides[J].Journal of Atomic&Molecular Physics,2015,32(1):61-64.
[24]Tong J B,Chen Y,Che T,et al.Quantitative structure activity relationship studies of anti-tuberculosis drug using three-dimensional structure descriptors[J].Journal of Atomic&Molecular Physics,2012,29(3):382-386.
[25]Xin Meiling(辛美玲),Chu Zhenhua(褚振华),Li Yu(李鱼).Molecular modification of polychlorinated biphenyl dihydroxy derivatives through molecular docking as sociated with CoMSIA/HQSAR models[J].Chemical Jouranl of Chinese Universities(高等学校化学学报),2018,39(2):299-309.
[26]Bhargava S,Adhikari N,Amin S A,et al.Hydroxyethylamine derivatives as HIV-1 protease inhibitors:A predictive QSARmodelling study based on monte carlo optimization[J].Sar&Qsar in Environmental Research,2017,28(12):1-18.
[2]Liu X,Wang H,Huwanbiao Z.Global stability of an HIVpathogenesis model with cure rate.[J].Nonlinear Analysis Real World Applications,2011,12(6):2947-2961.
[3]Meng Ge(孟歌),He Yanping(何严萍).Three dimensional quantitative structure-activity relationship of HEPT analogues as HIV-1 reverse transcriptase inhibitors[J].Chemical Jouranl of Chinese Universities(高等学校化学学报),2002,23(7):1304-1308.
[4]Meng Ge(孟歌),Chen Fener(陈芬儿).Research progress of HEPTanalogs as nonnucleoside HIV-1 reverse transcriptase inhibitors[J].Chinese Journal of Medicinal Chemistry(中国药物化学杂志),2004,14(1):56-64.
[5]Mandal A,Roy K.Predictive QSAR modeling of HIV reverse transcriptase inhibitor TIBO derivatives.[J].European Journal of Medicinal Chemistry,2009,44(4):1509-1524
[6]Lu P,Wei X R.Co MFA and CoMSIA studies on HIV-1 attachment inhibitors[J].European Journal of Medicinal Chemistry,2010,45(5):1792-1798.
[7]Heravi Y E,Sereshti H,Saboury A A,et al.3D QSAR studies,Pharmacophore modeling,and virtual screening of diarylpyrazolebenzenesulfonamide derivatives as a template to obtain new inhibitors,using human carbonic anhydraseⅡas a model protein[J].JEnzyme Inhib Med Chem,2017,32(1):688-700.
[8]Hu Songqing(胡松青),Mi Siqi(米思奇),Jia Xiaolin(贾晓林),et al.3D-QSAR study and molecular design of benzimidazole derivatives as corrosion inhibitors[J].Chemical Jouranl of Chinese Universities(高等学校化学学报),2011,32(10):2402-2409.
[9]Awasthi M,Singh S,Pandey V P,et al.CoMFA and CoMSIA-based designing of resveratrol derivatives as amyloid-beta aggregation inhibitors against alzheimer's disease[J].Medicinal Chemistry Research,2018,27(4):1-19.
[10]Magalh?es U O,Souza A M,Albuquerque M G,et al.Hologram quantitative structure-activity relationship and comparative molecular field analysis studies within a series of tricyclic phthalimide HIV-1integrase inhibitors[J].Drug Des Devel Ther,2013,7:953-961.
[11]Cheng Y,Zhou M,Tung C H,et al.Studies on two types of PTP1Binhibitors for the treatment of type 2 diabetes:Hologram QSAR for OBA and BBB analogues[J].Bioorganic&Medicinal Chemistry Letters,2010,20(11):3329-3337.
[12]Xiang Yuhong(相玉红),Xiao Aijing(肖爱婧),Zhang Zhuoyong(张卓勇).QSAR studies on a series of tetrahydroisoquinoline derivatixes by using CoMFA,CoMSIA,HQSAR[J].Journal of Lanzhou University(Natural Sciences)(兰州大学学报:自科版),2009,45(4):88-93.
[13]Noorizadeh H,Sajjadifar S,Farmany A.A quantitative structureactivity relationship study of anti-HIV activity of substituted HEPTusing nonlinear models[J].Medicinal Chemistry Research,2013,22(11):5442-5452.
[14]Tong J B,Li Y Y,Jiang G Y,et al.Application of an R-group search technique in the molecular design of dipeptidyl boronic acid proteasome inhibitors[J].Journal of the Serbian Chemical Society,2016,82:1025-1037.
[15]Shirota Y,Luo H,Qin W,et al.Hepatitis C virus(HCV)NS5A binds RNA-dependent RNA polymerase(RdRP)NS5B and modulates RNA-dependent RNA polymerase activity[J].Journal of Biological Chemistry,2002,277(13):11149-11155.
[16]Yu S,Yuan J,Shi J,et al.HQSAR and topomer CoMFA for predicting melanocortin-4 receptor binding affinities of trans-4-(4-chlorophenyl)pyrrolidine-3-carboxamides[J].Chemometrics&Intelligent Laboratory Systems,2015,146:34-41.
[17]Tenenhaus M,Vinzi V E,Chatelinc Y M,et al.PLS path modeling[J].Computational Statistics&Data Analysis,2005,48(1):159-205.
[18]Patel S,Stott IP,Bhakoo M,et al.Patenting computer-designed peptides[J].Journal of Computer-Aided Molecular Design,1998,12(6):543-556.
[19]Cherkasov A,Jankovic B.Application of'inductive'QSARdescriptors for quantification of antibacterial activity of cationic polypeptides[J].Molecules,2004,9(12):1034-1052.
[20]Fjell C D,Jenssen H,Kai H,et al.Identification of novel antibacterial peptides by chemoinformatics and machine learning[J].Journal of Medicinal Chemistry,2009,52(7):2006-2015.
[21]He Y,Yan W,Coito C,et al.The regulation of hepatitis C virus(HCV)internal ribosome-entry site-mediated translation by HCVreplicons and nonstructural proteins[J].Journal of General Virology,2003,84(3):535-543.
[22]Garcia-Saez I,Debonis S R,Trucco F,et al.Structure of human Eg5in complex with a new monastrol-based inhibitor bound in the Rconfiguration[J].Journal of Biological Chemistry,2007,282(13):9740-9747.
[23]Li M P,Zhang S W.Quantitative structure property relationship studies of the pKa values for sulfonamides[J].Journal of Atomic&Molecular Physics,2015,32(1):61-64.
[24]Tong J B,Chen Y,Che T,et al.Quantitative structure activity relationship studies of anti-tuberculosis drug using three-dimensional structure descriptors[J].Journal of Atomic&Molecular Physics,2012,29(3):382-386.
[25]Xin Meiling(辛美玲),Chu Zhenhua(褚振华),Li Yu(李鱼).Molecular modification of polychlorinated biphenyl dihydroxy derivatives through molecular docking as sociated with CoMSIA/HQSAR models[J].Chemical Jouranl of Chinese Universities(高等学校化学学报),2018,39(2):299-309.
[26]Bhargava S,Adhikari N,Amin S A,et al.Hydroxyethylamine derivatives as HIV-1 protease inhibitors:A predictive QSARmodelling study based on monte carlo optimization[J].Sar&Qsar in Environmental Research,2017,28(12):1-18.