Structure-based in silico and in vitro Analysis Reveals Asiatic Acid as Novel Potential Inhibitor of Mycobacterium tuberculosis Maltosyl Transferase

Aims: The present study aimed to search for novel potent inhibitor(s) against the recently discovered maltosyltransferase (GlgE) target of M.tb. Background: GlgE belongs to an a-amylase family and catalyzes the elongation of cytosolic branched alpha-glucan. Inactivation of M.tb. GlgE results in DNA damage and rapid death of M.tb. due to the accumulation of a toxic altosyl donor, maltose-1-phosphate (M1P), suggesting that GlgE is an intriguing target for inhibitor design. Methods: 1000 natural compounds were compiled from public databases and literature through virtual screening, of which 25 compounds were found to satisfy all drug-likeness properties and ADME/toxicity criteria, followed by molecular docking with GlgE. Compound(s) showing the lowest binding energy was further subjected to molecular dynamics simulation (MDS) and in vitro analysis. Results: Molecular docking analysis allowed the selection of 5 compounds with significant binding affinity to GlgE targets. Amongst these compounds, asiatic acid exhibited the lowest binding energy (-12.61 kcal/mol). The results of 20-ns MDS showed that asiatic acid formed a stable complex with GlgE. Additionally, asiatic acid exhibited in vitro anti-mycobacterial activity against M.tb. H37Ra, M. bovis BCG, and M. smegmatis strains. Conclusion: The study reveals asiatic acid as a promising anti-mycobacterial agent that might emerge as a novel natural anti-TB lead molecule in the future.