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.

In Vitro Study of Biological Activity of Tanacetum vulgare Extracts

“…From the modeling results, it can be concluded that the potentiation of the 2PD4 and 2GO4 enzymes can lead to an antibacterial effect against gamma-positive and Gram-negative bacteria. The results of molecular docking are in good agreement with the literature data on the study of the potentiation of the enzymatic targets of our choice using antibacterial drugs with new mechanisms of action [ 34 , 35 , 36 ]. Table 3 presents the scoring function (Gibbs energy in kcal/mol) to the corresponding compound end target.…”

Design and Preparation of Antimicrobial Agents

“…Furthermore, Singh et al [ 9 ] compiled a library of 80 compounds from Ruta graveolens and citrus plants belonging to the Rutaceae family for pharmacokinetic and molecular docking analyses. The chemical structures of the 80 phytochemicals and the 3D structure of the mycobacterial target InhA enzyme were obtained from the PubChem database and the RCSB Protein Data Bank, respectively.…”

Untitled

“…Until today, both INH and ETH are prodrugs available. They are activated by either KatG or EthA enzyme, respectively, generating a reactive oxygen species (ROS) that ultimately impairs InhA and disrupt mycolic acid chain elongation 13,14 .…”