Computational approaches: Atom-based 3D-QSAR, molecular docking, ADME-Tox, MD simulation and DFT to find novel multi-targeted Anti-tubercular agents

Abstract

Tuberculosis (TB) has become the biggest threat towards human society due to the rapid rise in resistance of the causative bacteria Mycobacterium tuberculosis (MTB) against the available anti-tubercular drugs. There is an urgent need to design new multi-targeted anti-tubercular agents to overcome the resistance species of MTB through computational design tools. With this aim in the present work, a combination of atom-based three-dimensional quantitative structure-activity relationship (3D-QSAR), six-point pharmacophore (AHHRRR), and molecular docking analysis was performed on a series of fifty-eight anti-tubercular agents. The generated QSAR model showed statistically significant correlation co-efficient R2, Q2, and Pearson r-factor of 0.9521, 0.8589, and 0.8988 respectively indicating good predictive ability. Molecular docking study was performed for the data set of compounds with the two important anti-tubercular target proteins, Enoyl acyl carrier protein reductase (InhA) (PDBID: 2NSD) and Decaprenyl phosphoryl-β-D-Ribose 20-epimerase (DprE1) (PDBID: 4FDO). Using the similarity search principle virtual screening was performed on 237 compounds retrieved from the Pubchem database to identify potent multitargeted anti-tubercular agents. The screened compound, MK3 showed the highest docking score of -9.2 and − 8.3 Kj/mol towards both the target proteins InhA and DprE1 were picked for 100ns molecular dynamic simulation study using GROMACS. From the data generated, the compound MK3 showed thermodynamic stability and effective binding within the active binding pocket of both target proteins without much deviation. The result of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) and energy gap analysis predicts the molecular reactivity and stability of the identified molecule. Based on the result of the above studies the proposed compound MK3 can be successfully used for the development of a novel multi-targeted anti-tubercular agent with high binding affinity and favourable ADME-T properties.