In Silico Investigation of Pyrrole-Based Compounds Targeting InhA for the Development of Novel Antitubercular Agents

Abstract:Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA) is a key enzymeinvolved in fatty-acid elongation and mycolic-acid biosynthesis, which is essential for the formation andintegrity of the mycobacterial cell wall. Therefore, InhA represents an important molecular target for thedevelopment of novel antitubercular agents. In the present study, pyrrole analogs were investigated usingan in silico structure-based drug design approach to identify potential InhA inhibitors.The purpose of thiswork was to undertake an in silico investigation of pyrrole compounds as possible InhA inhibitors in thecontext of tuberculosis.Pyrrole derivatives were drawn with ChemSketch, and the sdf (simple dimensionfile) format was produced using Open Babel software. The docking procedure made use of the crystalstructure of the InhA enzyme (PDB ID:6R9W), which was obtained from the RCSB Protein DataBank.The molecular docking investigations were conducted using AutoDock Tools 1.5.6. BioviaDiscovery Studio software version 2021 was used to visualize 2D and 3D docked structuralmolecules.Following this, the top 10 pyrrole derivatives with the greatest binding energy undertookADME, SAR, toxicity, and medicinal chemistry score studies.In the in silico investigation, isoniazid wasemployed as the standard medication.We extracted ligand molecules from Chemsketch, whereas the InhAenzyme, identified by its PDB ID:6R9W website (https://www.rcsb.org/) in pdb format We employedisoniazid as the reference medication in the molecular docking study. Among the 50 pyrrole derivativestested, 10 had the highest favourable binding energies to InhA. The top ten pyrrole compounds werefurther investigated in terms of pharmacokinetics and bioactivity. Both compounds C1 and C8 hadnotable docking scores of -10.4 and -10.0 Kcal/mol, respectively. Our analysis found that all 10 pyrrolederivatives displayed drug-like characteristics. The investigation revealed that pyrrole compounds may bedeveloped as efficient InhA inhibitors. The identified compounds may therefore be prioritized forsynthesis and subsequent in vitro antitubercular evaluation.