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
Current Topics in Medicinal Chemistry
Title:Drug Design and Identification of Potent Leads Against Mycobacterium tuberculosis Thymidine Monophosphate Kinase
Volume: 12 Issue: 7
Author(s): S. Van Calenbergh, S. Pochet and H. Munier-Lehmann
Affiliation:
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
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.
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Cite this article as:
Van Calenbergh S., Pochet S. and Munier-Lehmann H., Drug Design and Identification of Potent Leads Against Mycobacterium tuberculosis Thymidine Monophosphate Kinase, Current Topics in Medicinal Chemistry 2012; 12 (7) . https://dx.doi.org/10.2174/156802612799984580
DOI https://dx.doi.org/10.2174/156802612799984580 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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