Identification of Novel Inhibitor of Enoyl-Acyl Carrier Protein Reductase (InhA) Enzyme in Mycobacterium tuberculosis from Plant-Derived Metabolites: An In Silico Study

Abstract

Mycobacterium tuberculosis (M.tb.) enoyl-acyl carrier protein (ACP) reductase (InhA) is validated as a useful target for tuberculosis therapy and is considered an attractive enzyme to drug discovery. This study aimed to identify the novel inhibitor of the InhA enzyme, a potential target of M.tb. involved in the type II fatty acid biosynthesis pathway that controls mycobacterial cell envelope synthesis. We compiled 80 active compounds from Ruta graveolens and citrus plants belonging to the Rutaceae family for pharmacokinetics and molecular docking analyses. The chemical structures of the 80 phytochemicals and the 3D structure of the target protein were retrieved from the PubChem database and RCSB Protein Data Bank, respectively. The evaluation of druglikeness was performed based on Lipinski's Rule of Five, while the computed phytochemical properties and molecular descriptors were used to predict the ADMET of the compounds. Amongst these, 11 pharmacokinetically-screened compounds were further examined by performing molecular docking analysis with an InhA target using AutoDock 4.2. The docking results showed that gravacridonediol, a major glycosylated natural alkaloid from Ruta graveolens, might possess a promising inhibitory potential against InhA, with a binding energy (B.E.) of -10.80 kcal/mole and inhibition constant (Ki) of 600.24 nM. These contrast those of the known inhibitor triclosan, which has a B.E. of -6.69 kcal/mole and Ki of 12.43 µM. The binding efficiency of gravacridonediol was higher than that of the well-known inhibitor triclosan against the InhA target. The present study shows that the identified natural compound gravacridonediol possesses drug-like properties and also holds promise in inhibiting InhA, a key target enzyme of M.tb.

Keywords: FAS-II; InhA; Rutaceae family; gravacridonediol; molecular docking; tuberculosis.

Figure 4

Chemical structure of (a) gravacridonediol and (b) triclosan (COc1ccccc1).

Figure 1

(a) Docked pose of gravacridonediol in the InhA binding site, showing the molecular interactions—hydrogen and hydrophobic bonds noted using green and pink/purple dashed lines, respectively; (b) 2D plot of the interactions between gravacridonediol and key residues of InhA, generated by BIOVIA Discovery Studio visualizer; (c) docked pose of triclosan in the InhA binding site, showing molecular interactions—hydrogen and hydrophobic bonds noted using green and pink/purple dashed lines, respectively; (d) 2D plot of interactions between triclosan and key residues of InhA, generated by BIOVIA Discovery Studio visualizer.

Figure 2

RMSD plot for the docked complex of (a) Gravacridonediol-InhA (b) Triclosan- InhA.

Figure 3

Protein–ligand interaction plots for (a) gravacridonediol and (b) triclosan.