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Exploring acyclic nucleoside analogues as inhibitors of Mycobacterium tuberculosis thymidylate kinase

AuthorsFamiliar, Olga ; Munier-Lehmann, H.; Negri, Ana; Gago, Federico ; Douguet, D.; Rigouts, L.; Hernández, A. -I.; Camarasa Rius, María José ; Peréz-Pérez, María-Jesús
Issue Date2008
CitationChemMedChem 3: 1083- 1093 (2008)
AbstractIn the search for novel inhibitors of the enzyme thymidine monophosphate kinase of Mycobacterium tuberculosis (TMPKmt), an attractive target for novel antituberculosis agents, we report herein the discovery of the first acyclic nucleoside analogues that potently and selectively inhibit TMPKmt. The most potent compounds in this series are (Z)-butenylthymines carrying a naphtholactam or naphthosultam moiety at position 4, which display Ki values of 0.42 and 0.27 μM, respectively. Docking studies followed by molecular dynamics simulations performed to rationalize the interaction of this new family of inhibitors with the target enzyme revealed a key interaction between the distal substituent and Arg 95 in the target enzyme. The fact that these inhibitors are more easily synthesizable than previously identified TMPKmt inhibitors, together with their potency against the target enzyme, makes them attractive lead compounds for further optimization. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.
Identifiersdoi: 10.1002/cmdc.200800060
issn: 1860-7179
e-issn: 1860-7187
Appears in Collections:(IQM) Artículos
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