Binding of pyrazole-based inhibitors to Mycobacterium tuberculosis pantothenate synthetase: docking and MM-GB(PB)SA analysis

Recently, the search for new drugs against tuberculosis (TB) has been a hot topic and the search for new inhibitors against validated drug targets and pathways other than those currently targeted by known drugs is suggested to be the most promising way forward. Mycobacterium tuberculosis pantothenate synthetase (MTBPS) happens to be one of such targets. In a quest to carry out virtual screening for active inhibitors against MTBPS and to get ideas for the design of new inhibitors against this target, we have docked a set of pyrazole-based inhibitors to the active site of this enzyme. The docking solutions were post processed using the MM-PB(GB)SA method and molecular dynamic simulations in order to analyze and validate the two previously proposed binding modes. The results show that both the MM-PBSA and MM-GBSA were able to discriminate between active and inactive compounds. Moreover, the pharmacophore-based scoring method proved efficient in discriminating the active compounds from inactives. From this work a protocol for screening of potential inhibitors of the enzyme from commercially available databases has been devised.