Structural Basis for Inhibition of Mycobacterial and Human Adenosine Kinase by 7-Substituted 7-(Het)aryl-7-deazaadenine Ribonucleosides

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• 作者：Jan Sn谩拧el ; Petr Nau拧 ; Ji艡铆 Dost谩l ; Ale拧 Hn铆zda ; Jind艡ich Fanfrl铆k ; Ji艡铆 Brynda ; Aurelie Bourderioux ; Michal Du拧ek ; Hana Dvo艡谩kov谩 ; Ji艡ina Stola艡铆kov谩 ; Helena Z谩bransk谩 ; Radek Pohl ; Petr Kone膷n媒 ; Petr D啪ub谩k ; Ivan Votruba ; Mari谩n Hajd煤ch ; Pavl铆na 艠ez谩膷ov谩 ; V谩clav Veverka ; Michal Hocek ; Iva Pichov谩
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：October 23, 2014
• 年：2014
• 卷：57
• 期：20
• 页码：8268-8279
• 全文大小：546K
• ISSN：1520-4804

文摘

Adenosine kinase (ADK) from Mycobacterium tuberculosis (Mtb) was selected as a target for design of antimycobacterial nucleosides. Screening of 7-(het)aryl-7-deazaadenine ribonucleosides with Mtb and human (h) ADKs and testing with wild-type and drug-resistant Mtb strains identified specific inhibitors of Mtb ADK with micromolar antimycobacterial activity and low cytotoxicity. X-ray structures of complexes of Mtb and hADKs with 7-ethynyl-7-deazaadenosine showed differences in inhibitor interactions in the adenosine binding sites. 1D ¹H STD NMR experiments revealed that these inhibitors are readily accommodated into the ATP and adenosine binding sites of Mtb ADK, whereas they bind preferentially into the adenosine site of hADK. Occupation of the Mtb ADK ATP site with inhibitors and formation of catalytically less competent semiopen conformation of MtbADK after inhibitor binding in the adenosine site explain the lack of phosphorylation of 7-substituted-7-deazaadenosines. Semiempirical quantum mechanical analysis confirmed different affinity of nucleosides for the Mtb ADK adenosine and ATP sites.