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Current Computer-Aided Drug Design

Editor-in-Chief

ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

Research Article

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

Author(s): Kratika Singh, Akanksha Sharma, Tarun Kumar Upadhyay, Mohammad Hayat-ul-Islam, M. Kalim A. Khan, Upendra N. Dwivedi and Rolee Sharma*

Volume 18, Issue 3, 2022

Published on: 17 August, 2022

Page: [213 - 227] Pages: 15

DOI: 10.2174/1573409918666220623105908

Price: $65

Abstract

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 α-amylase family and catalyzes the elongation of cytosolic branched α-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 withsignificant 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.

Keywords: Tuberculosis, maltosyltransferase, molecular docking, molecular dynamic simulation, anti-TB, natural compounds.

Graphical Abstract

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