In Silico Identification of Cinnamonol as a Potential FAS-II Pathway Inhibitor Targeting Mycolic Acid Biosynthesis in Mycobacterium tuberculosis from Phytochemicals Present in Hawan Samagri

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) infection, is increasingly challenged by the emergence of multidrug-resistant strains, necessitating the development of novel therapeutic strategies. This study aimed to identify natural phytochemicals from Hawan Samagri, a traditional Ayurvedic polyherbal mixture, with the potential to inhibit multiple enzymes of the fatty acid synthase II (FAS-II) pathway, a critical target for mycolic acid biosynthesis in M.tb. Plants constituting Hawan Samagri were first identified through Ayurvedic literature and subsequently screened using Dr. Duke’s Phytochemical and Ethnobotanical Database to retrieve reported phytochemicals. Compounds not previously reported for antimycobacterial activity were selected and further filtered using Lipinski’s Rule of Five and ADMET analysis. These shortlisted phytochemicals were then subjected to molecular docking against three key FAS-II enzymes-HadAB, FabG1, and KasA followed by molecular dynamics (MD) simulations to evaluate binding stability and interactions with catalytic and cofactor-binding residues. The analysis identified five promising compounds Cinnamonol, Episesamin, Norhyoscine, Apohyoscine, and Chrysophanol exhibiting strong binding affinities and stable interactions across the targeted enzymes. Among these, Cinnamonol demonstrated the most significant multitarget binding potential along with high stability during extended molecular dynamics simulations, indicating its promise as a broad-spectrum FAS-II inhibitor. Overall, this integrative in silico approach provides scientific validation for the traditional use of Hawan Samagri by identifying and characterizing its phytochemicals as potential multitarget inhibitors of the FAS-II pathway in M.tb, with Cinnamonol emerging as a particularly promising lead candidate for future anti-TB drug development due to its favorable pharmacokinetic properties and mechanistic relevance to fatty acid metabolism.