Drug repurposing approach against Mycobacterium tuberculosis Enoyl-[acyl-carrier-protein] reductase: insight from molecular dynamics simulations

Abstract

ABSTRACT Enoyl-[acyl-carrier-protein] reductase (InhA) is one of the major targets for the inhibition of Mycobacterium tuberculosis (Mtb). Herein, we introduce a drug repurposing approach against Mtb-InhA: Insight from molecular dynamic simulations. The approach was found hopeful to identify in silico hits with better binding affinities as compared to isoniazid. Four drug hits displayed higher total binding energies (ΔG tot) in relation to isoniazid with DB04007 exhibiting the highest ΔG tot of −41.11 kcal/mol as compared to the −7.89 kcal/mol from isoniazid. Herein, the results revealed that the isoniazid is less stable compared to DB04007. Hence, this pattern was reiterated by the lower RoG of DB04007. Both DB04007 and isoniazid exhibited a structural evolution denoted to common flexibility changes. A distinct increase in fluctuation was seen in the RMSF of DB04007 which could be attributed to Ser92 forming 2 hydrogen bonds with the inhibitor, the distal amino acids affecting stability and the evolution of residues 195-210 from a primary to a secondary structure. DB04007 exhibited a higher total binding free energy due to the residual van der Waals and hydrogen bonding interactions as compared to the isoniazid. This approach can potentially serve as a platform for the development and discovery of novel drugs.