Objective/background: Mycobacterium tuberculosis thymidine monophosphate kinase (mtTMPK) is a potential enzymatic target for the treatment of tuberculosis (TB).
Materials and methods: In this study, we performed pharmacophore-based in silico screening, targeting mtTMPK with a compound library of 461,383 chemicals. We evaluated the candidate compounds for inhibitory effects on the growth of the model mycobacteria, Mycobacterium smegmatis.
Results: The compound KTP3 completely inhibited the growth of M. smegmatis at 100 μM. A similarity search and rescreening with the structure of compound KTP3 using a web-based database identified two similar compounds (KTPS1 and KTPS2) with improved potency. The KTP3 analogs, KTPS1 and KTPS2, exhibited strong growth inhibitory effects with half-maximal inhibitory concentration values of 8.04 μM and 17.1 μM, respectively, against M. smegmatis. Moreover, the most potent chemical compound, KTPS1, did not exhibit toxic effects on the model enterobacteria and several mammalian cells. Two active chemicals, KTPS1 and KTPS2, inhibited mtTMPK activity by 18% and 36%, respectively, suggesting that these compounds have off-target activities against Mycobacterium.
Conclusion: Structural and biological information on these chemicals is likely to be useful for the development of novel antibiotics for the treatment of TB.