Induced fit docking, free energy calculation and molecular dynamics studies on Mycobacterium tuberculosis alanine racemase inhibitor. Issue 5 (24th March 2018)

• Record Type: Journal Article
• Authors: Azam, Mohammed Afzal; Jayaram, Unni
• Is Part Of: Molecular simulation. Volume 44:Issue 5(2018)
• Page Start: 424
• Page End: 432
• Publication Date: 2018-03-24
• Subjects: Alanine racemase -- induced fit docking -- binding free energy -- MD simulation; Molecular dynamics -- Computer simulation -- Periodicals; Statistical mechanics -- Computer simulation -- Periodicals; 539.6
• DOI: 10.1080/08927022.2017.1393811
• Languages: English
• ISSNs: 0892-7022

Abstract

Abstract: Alar, a Pyridoxal 5′-phosphate (PLP)-dependent bacterial enzyme is responsible for the racemisation of L-alanine into D-alanine which is essential for the peptidoglycan biosynthesis in both Gram-positive and Gram-negative bacteria. In the present study, we performed induced fit docking, binding free energy calculation and molecular dynamics simulation to elucidate the Alar inhibition potential of 1, 2, 4-thiadiazolidine-3, 5-dione-based inhibitor1 . The inhibitor binds to the hydrophobic groove of Alar and the binding was found to be stable throughout 20-ns MD simulation. Induced fit docking result showed that Lys42, Tyr46, Tyr175 and Tyr364 residues are primarily responsible for the stabilisation of inhibitor–protein complex. Further, high negative van der Waals binding free energy value of –38.88 kcal/mol, indicated it as the main driving force for the inhibitor binding. Based on the information obtained from this study, we designed few molecules as potent Alar inhibitor. In order to gain structural insight and to validate the stability of complex, we performed 20-ns MD simulation of the designed moleculeD1 . Results obtained from this study can be used for the design of M. tuberculosis Alar potent inhibitors lacking affinity for the co-factor PLP.