Targeting KasA: isosakuranetin derivatives as promising scaffolds for novel anti-tuberculosis agents against drug-resistant Mycobacterium tuberculosis.

Mycobacterium tuberculosis remains a major global health threat due to the rising prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, which limit the effectiveness of current therapies. The ß-keto-acyl carrier protein synthase (KasA), a key enzyme in the FAS-II pathway for mycolic acid biosynthesis, is a promising target for new anti-tuberculosis agents. Chromolaena odorata, a medicinal plant with reported antimicrobial and antituberculosis activity, is a rich source of bioactive flavonoids, including Isosakuranetin, which shows moderate anti-tuberculosis activity. Modifications in pharmacophores-such as functional groups, structural features, bond angles, and bond distances-can enhance the activity of these phytochemicals and improve their potential as drug leads. A structure-based computational workflow was employed, including molecular docking, MM-GBSA binding energy calculations, ADMET evaluation, and 250 ns molecular dynamics simulations to investigate the binding affinity, stability, and pharmacokinetic profiles of Isosakuranetin and its derivatives against KasA. The analysis revealed differential binding affinities and dynamic stabilities of Isosakuranetin derivatives. Isn_96 exhibited the strongest binding affinity (-7.921 kcal/mol), with favorable electrostatic and hydrophobic interactions involving residues HIS311, HIS345, and ASP273. Post-MDS MM-GBSA analysis confirmed its enhanced stability, displaying the highest binding free energy (-56.20 ± 6.90 kcal/mol). Pharmacokinetic predictions also indicated acceptable absorption and safety profiles. These findings suggest that Isosakuranetin derivatives, particularly Isn_96, are promising scaffolds for the design of novel KasA inhibitors. Their strong binding affinity, dynamic stability, and favorable ADMET properties highlight potential efficacy against drug-resistant M. tuberculosis. The results emphasize the potential of plant-derived flavonoids as lead compounds and underscore the value of structure-based computational approaches in guiding anti-tuberculosis drug development.