RESUMEN
Mucormycosis, a life-threatening fungal infection that primarily affects immunocompromised individuals.The protein family commonly observed in the fugus responsible for causing Mucormycosis. The attachment of spores to host cells surface, facilitated by a protein CotH, is a critical step for the invasion and progression of the disease. Therefore, CotH inhibitors have emerged as a promising therapeutic strategy for treating mucormycosis.This study presents a novel therapeutic target and ligand for controlling the growth of Mucorales. First, to identify potential CotH inhibitors, we surveyed a library antifungal compounds elaborated in AYUSearch database. Next, using machine learning-based algorithms we screend 20 potentials ligands, followed by structure-based molecular modelling and molecular trajectory analysis to identify the three most promising chemical constituents. In-vitro tube assays on selected Mucorales determined the minimum inhibitory concentrations (MIC) for screened chemotypes. The MIC assay revealed that Bacoside inhibits the growth and sporulation at 5 mg/ml concentrations, emerging as a probable CotH inhibitor. Further, the compound's toxicity was evaluated by adding it to the feed of C.elegans, and the finding suggests that the bacoside is reasonably safe at the studied concentration. The findings project bacoside A as a potential anti-mucorale lead compound that can be further validated with preclinical and clinical studies.
RESUMEN
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.
RESUMEN
Achillea millefolium (Yarrow) is a herbaceous plant of Greek origin noted to treat pneumonia, common cold, cough, and other respiratory disorders. The flowers and leaves are the core part used to prepare herbal tea that gains the world's recognition as medicinal tea. Coronavirus disease is spreading across the globe, and numerous approaches are lodged to treat virus-induced lung inflammation. Here, we used the network pharmacology, metabolite analysis, docking and molecular simulation and MM-PBSA analysis to comprehend the biochemical basis of the health-boosting impact of Yarrow tea. Next, we performed the microscopic and dynamic light scattering (DLS) analysis of yarrow-treated ChAdOx1 nCoV-19 to evaluate the virucidal activity of the Yarrow. The present study investigates the druggability, metabolites and potential interaction of the title tea with genes associated with Covid-19-induced pathogenesis. Towards this, 1022 gene hits were obtained, 30 are mutually shared. Network Pharmacology and microarray gene expression analysis find the connection of PTGS2 in relieving the virus-induced inflammation. Yarrow constituents Luteolin may inhibit or down-regulate the Cyclooxygenase II (PTGS2), a plausible mechanism underlying the Yarrow's anti-inflammatory actions. Further, the Yarrow's virucidal activity was assessed towards Transmission Electron Microscopic (TEM). The Yarrow treated SARS-nCoV-2 cell exhibits the disintegration of the virus membrane. This work provides a scientific basis for further elucidating the mechanism underlying Achillea millefolium's antiviral and anti-inflammatory properties.
