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

0436116 - ÚOCHB 2015 RIV US eng J - Journal Article
Snášel, Jan - Nauš, Petr - Dostál, Jiří - Hnízda, Aleš - Fanfrlík, Jindřich - Brynda, Jiří - Bourderioux, Aurelie - Dušek, Michal - Dvořáková, H. - Stolaříková, J. - Zábranská, Helena - Pohl, Radek - Konečný, P. - Džubák, P. - Votruba, Ivan - Hajdúch, M. - Řezáčová, Pavlína - Veverka, Václav - Hocek, Michal - Pichová, Iva
Structural Basis for Inhibition of Mycobacterial and Human Adenosine Kinase by 7-Substituted 7-(Het)aryl-7-deazaadenine Ribonucleosides.
Journal of Medicinal Chemistry. Roč. 57, č. 20 (2014), s. 8268-8279. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA ČR GAP207/11/0344; GA MŠMT LO1302; GA MŠMT(CZ) LK11205
EU Projects: European Commission(XE) 241587 - SYSTEMTB
Grant - others:GA MŠk(CZ) LM2011020
Institutional support: RVO:61388963 ; RVO:68378271
Keywords : 7-(het)aryl-7-deazaadenine ribonucleosides * enzyme inhibition * adenosine kinase * cytostatic activity
Subject RIV: CC - Organic Chemistry
Impact factor: 5.447, year: 2014

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 H-1 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.
Permanent Link: http://hdl.handle.net/11104/0239959