title: Exploring acyclic nucleoside analogues as inhibitors of Mycobacterium tuberculosis thymidylate kinase.
abstract: In 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 K(i) values of 0.42 and 0.27 microM, 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.
authors.affiliation: Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Familiar
authors.forename: Hélène
authors.initials: H
authors.lastname: Munier-Lehmann
authors.forename: Ana
authors.initials: A
authors.lastname: Negri
authors.forename: Federico
authors.initials: F
authors.lastname: Gago
authors.forename: Dominique
authors.initials: D
authors.lastname: Douguet
authors.forename: Leen
authors.initials: L
authors.lastname: Rigouts
authors.forename: Ana-Isabel
authors.initials: AI
authors.lastname: Hernández
authors.forename: María-José
authors.initials: MJ
authors.lastname: Camarasa
authors.forename: María-Jesús
authors.initials: MJ
authors.lastname: Pérez-Pérez
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors*; D009705:Nucleosides / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D009705:Nucleosides; C031721:naphthalene; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase