In silico development of potential InhA inhibitors through 3D-QSAR analysis, virtual screening and molecular dynamics

Tuberculosis is one of the most ancient infectious diseases known to mankind predating upper Paleolithic era. In the current scenario, treatment of drug resistance tuberculosis is the major challenge as the treatment options are limited, less efficient and more toxic. In our study we have developed an atom based 3D QSAR model, statistically validated sound with R2 > 0.90 and Q2 > 0.72 using reported direct inhibitors of InhA (2018-2022), validated by enzyme inhibition assay. The model was used to screen a library of 3958 molecules taken from Binding DB and candidates molecules with promising predicted activity value (pIC50) > 5) were selected for further analyzed screening by using molecular docking, ADME profiling and molecular dynamic simulations. The lead molecule, ZINC11536150 exhibited good docking score (glideXP = -11.634 kcal/mol) compared to standard triclosan (glideXP = -7.129 kcal/mol kcal/mol) and through molecular dynamics study it was observed that the 2nv6-complex of ZINC11536150 with Mycobacterium tuberculosis InhA (PDB entry: 2NV6) complex remained stable throughout the entire simulation time of 100 ns.

Automated summary

In this study, an atom-based 3D QSAR model was developed to screen potential candidates for the treatment of drug-resistant tuberculosis. Through molecular docking, ADME profiling, and molecular dynamic simulations, the lead molecule ZINC11536150 was found to exhibit strong antibacterial activity and stability.