Adewumi, AT, Oluyemi, WM, Adekunle, YA, Adewumi, N, Alahmdi, MI, Soliman, MES and Abo-Dya, NE (2023) Propitious Indazole Compounds as β-ketoacyl-ACP Synthase Inhibitors and Mechanisms Unfolded for TB Cure: Integrated Rational Design and MD Simulations. ChemistrySelect, 8 (3). ISSN 2365-6549

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Abstract

Mycobacterium tuberculosis β-ketoacyl-ACP synthase I (KasA) involves in mycolic acid biosynthesis for cell wall maintenance; hence, it is a critical target in TB drug design. Thiolactomycin (TLM) and derivatives are the known standard KasA enzyme activity inhibitors. However, TLM analogues have poor activity against KasA protein. Indazole sulphonamide chemotype (JSF-3285/JFX) was recently reported as a promising KasA enzyme inhibitor. JSF-3285 mechanism is unclear; thus, it provides a means for designing KasA inhibitors. This study unfolds six hits as unprecedented KasA inhibitors. The inhibitory mechanisms of the screened compounds were investigated and compared with a standard inhibitor (TLM) using integrated molecular informatics and dynamics. JFX, M1, M2, and M5 molecules showed stronger interactions with KasA, having binding energy (kcal/mol) of −44.05, −41.52, −39.51, and −35.9, respectively, against −11.69 for TLM. Molecules showed good predicted inhibitory constants, drug-likeness, ADME, and synthetic accessibility. KasA complex C-α atoms RMSD and RMSF showed stable and erratic fluctuations compared to apo KasA. The findings provide potential antimycobacterial lead-like molecules for future TB drugs.

Item Type:	Article
Uncontrolled Keywords:	3404 Medicinal and Biomolecular Chemistry; 34 Chemical Sciences; Emerging Infectious Diseases; Rare Diseases; Biodefense; Orphan Drug; Infectious Diseases; Tuberculosis; Biotechnology; 5.1 Pharmaceuticals; Infection; 03 Chemical Sciences; 34 Chemical sciences
Subjects:	R Medicine > R Medicine (General) R Medicine > RS Pharmacy and materia medica
Divisions:	Pharmacy and Biomolecular Sciences
Publisher:	Wiley
SWORD Depositor:	A Symplectic
Date Deposited:	09 Apr 2025 14:47
Last Modified:	09 Apr 2025 14:47
DOI or ID number:	10.1002/slct.202203877
URI:	https://researchonline.ljmu.ac.uk/id/eprint/26144

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