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- Title
Asiaticoside A for the modulation of 1-TbAd- a potential target and ligand for extensive drug resistance Mycobacterium tuberculosis.
- Authors
Tilwani, Komal; Patel, Abhishek; Patel, Mainavi; Sojitra, Pankaj; Dave, Gayatri
- Abstract
In nature, terpene nucleosides are relatively rare, with 1-tuberculosinyladenosine (1-TbAd) being an exclusive feature of Mycobacterium tuberculosis (Mtb). The convergence of nucleosides and terpene pathways in the Mtb complex appears to have emerged late in its evolutionary history. 1-TbAd (PDB ID: 3WQK) is a prominent chemical marker for Mtb and may contribute to its virulence-related properties when exported extracellularly. We gathered a comprehensive set of 270 phytochemicals from diverse Ayurvedic texts and treatment traditions. Subsequently, we conducted structure-based molecular docking analyses to identify compounds exhibiting the strongest binding affinity for 1-TbAd, highlighting their potential as drug candidates. These selected compounds were further subjected to an in-vitro growth inhibition assay against the reference strain Mycobacterium tuberculosis h37rv. Among the candidates, Asiaticoside A (ASA) emerged as a promising candidate from the pool of 270 compounds. To assess the impact of ASA on 1-TbAd expression, we employed a PCR-based mRNA expression assay, revealing ASA's ability to downregulate 1-TbAd expression in extensively drug-resistant MTb strains. Remarkably, the conventional drug rifampin showed no such effectiveness in our experiments. We further conducted molecular dynamic simulations to explore the interaction between ASA and 1-TbAd in a cellular-like environment, confirming the stability of their interaction. Also, we predicted ASA's stability toward causing inducing the random mutations in the target gene. With this, we propose a novel target and its modulator to treat extensively drug-resistant MTB. Key points: In-silico screening studies for identifying the hit compound mRNA expression analysis for validation of hit compound Random in-silico mutagenesis and Molecular dynamic simulation studies for evaluating the efficiency of Asiaticoside A.
- Subjects
MYCOBACTERIUM tuberculosis; DRUG resistance; GENE expression; DYNAMIC simulation; NUCLEOSIDES
- Publication
AMB Express, 2023, Vol 13, Issue 1, p1
- ISSN
2191-0855
- Publication type
Article
- DOI
10.1186/s13568-023-01616-w