Drug Design and Identification of Potent Leads Against Mycobacterium tuberculosis Thymidine Monophosphate Kinase

S.      Van Calenbergh; S.      Pochet; H.      Munier-Lehmann

Abstract

Antiviral chemotherapy often relies on nucleoside analogues, which, once phophorylated by intracellular kinases, target viral polymerases impeding DNA synthesis. In contrast, nucleoside analogues are much less explored as antibacterial drugs. Thymidine monophosphate kinase from Mycobacterium tuberculosis (TMPKmt), which is essential to DNA replication, was selected as a promising target for the design of new inhibitors. This review describes stepwise modifications of the TMPKmt substrate, guided by the feedback of enzyme assays and crystallographic analysis to afford potent enzyme inhibitors some of which also exhibited antitubercular activity. More importantly, several of the reported thymidine analogues provided a deeper understanding of the structure and catalytic mechanism of this intriguing enzyme.

Keywords: Tuberculosis, kinase, nucleotide metabolism, inhibitors, structure-activity relationship, molecular modeling, Antiviral chemotherapy, enzyme assays, antibacterial drugs, intriguing enzyme, demographic factors, potent enzyme inhibitors, cancer chemotherapy, antimycobacterial drugs