In Silico Discovery of Low-Toxicity Natural Ligands for Mycobacterial InhA: A Strategy Against Viral and Bacterial Co-Infections

Background: Tuberculosis (TB) remains a global challenge, intensified by drug resistance and HIV co-infection. Targeting enoyl-ACP reductase (InhA), vital for mycolic acid synthesis in Mycobacterium tuberculosis, is a promising approach. Natural products like flavonoids and alkaloids offer potential due to their bioactivity and structural diversity. Methods: Molecular docking and in silico ADMET/toxicity predictions were used to evaluate kaempferol (flavonoid) and berberine (alkaloid). InhA’s crystal structure (PDB ID: 4TZK) was the target. Ligands were prepared and minimized using MMFF94s in Avogadro, and docking was done via AutoDock Vina. pkCSM, SwissADME, and ProTox-II assessed pharmacokinetics and toxicity Results: Kaempferol showed stronger binding affinity (–7.1 kcal/mol) than berberine (–6.8 kcal/mol), interacting with residues like Glu219 and Trp230. Both formed stable hydrogen bonds and  pi-pi interactions. ADMET predictions favored kaempferol, indicating good oral bioavailability and low toxicity, while berberine showed immunotoxic and genotoxic potential. Conclusion: Kaempferol is the more promising candidate for InhA inhibition due to its higher binding affinity and favorable safety profile, warranting further optimization and experimental validation for TB treatment. How to cite this article: Abdulsahib A M J, Al-Hussainy A F, Ali H H, Abdulwahid A S, Hamzah H F, Tuama S J, Zainab H A7, Kadhim W D. In Silico Discovery of Low Toxicity Natural Ligands for Mycobacterial InhA: A Strategy Against Viral and Bacterial Co-Infections. J Commun Dis. 2025;57(2):67-73. DOI: https://doi.org/10.24321/0019.5138.202539