Identification of inhibitors against α-Isopropylmalate Synthase of Mycobacterium tuberculosis using docking-MM/PBSA hybrid approach

alpha-Isopropylmalate Synthase (alpha-IPMS) encoded by leuA in Mycobacterium tuberculosis (M.tb) is involved in the leucine biosynthesis pathway and is extremely critical for the synthesis of branched-chain amino acids (leucine, isoleucine and valine). alpha-IPMS activity is required not only for the proliferation of M.tb but is also indispensable for its survival during the latent phase of infection. It is absent in humans and is widely regarded as one of the validated drug targets against Tuberculosis (TB). Despite its essentiality, any study on designing of potential chemical inhibitors against alpha-IPMS has not been reported so far. In the present study, in silico identification of putative inhibitors against alpha-IPMS exploring three chemical databases i.e. NCI, DrugBank and ChEMBL is reported through structurebased drug design and filtering of ligands based on the pharmacophore feature of the actives. In the absence of experimental results of any inhibitor against alpha-IPMS, a stringent validation of docking results is done by comparing with molecular mechanics/PoissonBoltzmann surface area (MM/PBSA) calculations by investigating two more proteins for which experimental results are known.