title: Structure-aided design of inhibitors of Mycobacterium tuberculosis thymidylate kinase.
abstract: Antiviral chemotherapy often relies on nucleoside analogues, which, once phophorylated by intracellular kinases, target viral polymerases and preclude DNA synthesis. In contrast, common antibacterial drugs are rarely related to such compounds. In this work TMPKmt, which is essential to DNA replication, was selected as a promising target for inhibitor design. Our work demonstrates that judicious and stepwise modifications of the substrate structure of TMPKmt, guided by the feedback of the enzyme assays as well as by the enzyme's X-ray structure, proved a valuable approach to produce a submicromolar inhibitor of this target enzyme. This inhibitor was also capable to inhibit bacterial growth. Perhaps more importantly, some of the reported thymidine analogues also represent valuable tools to better understand the structure and the mechanism of this intriguing enzyme.
authors.affiliation: Laboratorium voor Medicinale Chemie-Vakgroep Geneesmiddelenleer, Faculteit Farmaceutische Wetenschappen, Universiteit Gent Harelbekestraat 72, B-9000 Gent.
authors.forename: S
authors.initials: S
authors.lastname: Van Calenbergh
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase