| Summary: | Tuberculosis (TB) is one of the leading causes of death worldwide. The development of new anti-tubercular drugs is required as resistant strains of M. tuberculosis to various first-line drugs are currently available. In this study, different fragments and functional groups were used to modify 5-Pentyl-2-phenoxyphenol (5PP) drug. Density functional theory was utilized for the geometric optimization of the modified drug structures. Flexible docking of the parent and all modified drugs was performed against Mycobacterium Enoyl ACP Reductase (2B36) to calculate and compare their binding affinities and non-covalent interactions. Increased non-bonded interactions along with improved binding energy are visualized for the modified drugs (J1, J2, and J3) compared to those for the parent drug J. All the modified drugs remain stably bound to the binding pocket of InhA after 100ns MD simulation. Binding free energy calculation from MD simulation also shows stable binding of the drugs with the target protein. Ensemble-based molecular docking was further performed to account for the receptor dynamics and flexibility. Variation in binding energy for a drug-protein complex is observed when protein flexibility is taken into consideration. Moreover, we found that residues Ala157, Tyr158, Ala198, Met199, and Ile215 of protein InhA are important for drug-protein interaction. Improved pharmacokinetic properties are also observed for the modified drugs compared to those for 5PP.
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