Drug binding analysis against a novel target in tuberculosis- a molecular dynamics approach

Abstract

Mycobacterium tuberculosis is a deadly human pathogen and causes the pulmonary disease, tuberculosis (TB). Current treatment programs to ght against TB is under threat due to the emergence of Multidrug Resistance (MDR) TB and Extensively drug Resistance (XDR) TB and also due to the co-existence of HIV-TB infection. So, there is a need and urgency to develop new and potent drugs to ght against this disease. As a part of our e orts in the development of new anti-tubercular leads, some potent tetrahydropyrazolo [1,5-a] pyrimidine-3-carboxamide (THPP) analogues were recently identi ed against Mycobacterium tuberculosis through a high- throughput whole-cell screening campaign. In this project, we are studying di erent analogues of THPP by computational molecular dynamics method and calculating the binding free energy of each inhibitor with the M.tuberculosis protein EchA6. Our main aim is to study which inhibitor binds strongly with the protein, which can help in the design of new and novel drugs that can treat tuberculosis disease. In this study, we used the AMBER force eld for protein and General Amber Force eld for the ligand, and we ran Molecular Dynamic Simulation for 100 ns. We used Molecular Mechanics- Poisson Boltzmann Surface Area method to calculate the free energy of binding, and we did normal mode analysis for calculating entropy contribution to the free energy. Our study suggests that binding is mainly driven by the Van der Waals interaction. This has to be considered for drug designing. Through our MM-PBSA results, we found out that the binding a nity of EchA6 with the ligand GSK951A and GSK572A is high due to its higher binding free energy. So, this result might be helpful for designing new and more potent drugs to combat TB.