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

Abstract

Antiviral chemotherapy often relies on nucleoside analogues, which, once phophorylated by intracellular kinases, target viral polymerases and preclude DNA synthesis. In contrast, nucleoside analogues are much less explored as antibacterial drugs. TMPKmt, which is essential to DNA replication, was selected as a promising target for inhibitor design. This review will describe how stepwise modifications of the enzyme's substrate, guided by the feedback of the enzyme assays as well as crystallographic information, proved a valuable approach to produce potent TMPKmt inhibitors, some of which were 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.

1-(Piperidin-3-yl)thymine amides as inhibitors of M. tuberculosis thymidylate kinase

“…Thymidine monophosphate kinase (TMPK), an enzyme at the junction of the de novo (involving thymidylate synthase) and salvage pathway, is responsible for the conversion of thymidine monophosphate (TMP) to thymidine diphosphate (TDP) 5 , 6 . Further phosphorylation leads to the formation of thymidine triphosphate (TTP), which is indispensable for DNA synthesis 7 .…”

Insights into Phosphate Cooperativity and Influence of Substrate Modifications on Binding and Catalysis of Hexameric Purine Nucleoside Phosphorylases

“…They are among the first cytotoxic molecules to be used in the treatment of cancer [20] and have been studied as potential drugs against tuberculosis [21], [22], malaria [7], [23], trichomoniasis [24] and schistosomiasis [25]. The chemical synthesis of these compounds is generally a costly multistep process that includes several protection and deprotection stages [13], [26].…”

Targeting tuberculosis using structure-guided fragment-based drug design

“…Thymidylate kinase (TMK), an enzyme involved in DNA synthesis that produces thymidine 5ʹ-diphosphate from ATP and thymidine 5ʹ-monophosphate, has been found to be essential for M. tuberculosis [53]. Target-focused drug discovery campaigns performed on this enzyme have identified some inhibitors but all of the compounds obtained were either thymidine monophosphate analogs or contained a thymidine moiety [53]. Naik and colleagues performed a fragment screen using NMR and a biochemical assay that led to identification of new scaffolds inhibiting TMK [54].…”