Design of Phenyl Keto Butanoic Acid Derivatives as Inhibitors against Malate Synthase of M.Tuberculosis based on Docking & MD Simulation Studies

Abstract

The emergence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb) has intensified efforts to discover novel drugs for tuberculosis (TB) treatment. Targeting the persistent state of Mtb, a condition in which Mtb is resistant to conventional drug therapies, is of particular interest. Persistent bacterial population relies on metabolic pathways that become active in low nutrient environment like glyoxylate shunt. Since the glyoxylate shunt enzymes are not present in mammals, they make attractive drug targets. This study is focused on malate synthase (MS), one of the enzymes in the glyoxylate shunt. Computational approach was used to identify potential inhibitors of MS. Crystal structure of MS (PDB ID-1N8I) in complex with inhibitor was used to rationally design better MS inhibitors. PKBA is identified to be potent inhibitor of malate synthase enzyme. 30 molecules were designed based on malate (product of Malate Synthase) and Phenyl keto butanoic acid (PKBA) backbone. All molecules were screened based on the lowest energy with repeated conformation of ligands, and passed through ADME/tox filters to sort out the toxic compounds. Molecular docking of all designed molecules with the receptor protein (malate synthase) was performed. The binding energy and inhibitory concentration was observed. On the basis of this study, the best molecule having the lowest binding energy and inhibitory concentration was identified. The best molecule identified was further evaluated by molecular dynamics simulation of protein-ligand complex in water solvent model. The rmsd close to 2 A◦ shows the stability of the complex. Inhibitors against MS have been identified and characterized for further development into potential novel anti-tubercular drugs.