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

Ali M Jaafar  Abdulsahib; Ali Fawzi Al-Hussainy; Halah Hussein Ali; Alzahraa S Abdulwahid; Hamza Fadhel Hamzah; Safa Jasim Tuama; Zainab H A; Wael Dheaa Kadhim

Ali M Jaafar Abdulsahib Department of Pharmacology, College of Pharmacy, University of Al-Ameed, Iraq - Karbala, Iraq
Ali Fawzi Al-Hussainy College of Pharmacy, Ahl Al Bayt University, Kerbala, Iraq
Halah Hussein Ali Department of Pharmacy, Al-Turath University, Baghdad, Iraq
Alzahraa S Abdulwahid Al-Hadi University College, Baghdad, Iraq
Hamza Fadhel Hamzah Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
Safa Jasim Tuama College of Health and Medical Technologies, National University of Science and Technology, Dhi Qar, Iraq
Zainab H A Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
Wael Dheaa Kadhim Mazaya University College, Iraq

Keywords: Tuberculosis; Communicable diseases; InhA enzyme; Mycobacterium tuberculosis; Flavonoids; Alkaloids

Abstract

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

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