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- Background/ Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the resistant pathogenic microorganisms that poses a global health threat due to its resistance to β-lactam antibiotics, where the protein penicillin-binding protein 2a (PBP2a) plays a crucial role in its resistance. This study explores the potential of phytochemicals from Uvaria chamae, a plant with known medicinal properties, to serve as dual-site inhibitors of PBP2a, targeting both the active and allosteric sites. Methods: Phytochemicals previously identified in U. chamae were subjected to molecular docking and molecular dynamics simulations to evaluate their binding affinities and stability at PBP2a’s active and allosteric sites. The compounds’ pharmacokinetic profiles were predicted in silico using SwissADME tools. Root-mean-square deviation (RMSD), radius of gyration, and binding free energy were analyzed for dynamic stability. Results: Among the evaluated compounds, Uvarinol and Dichamanetin demonstrated high binding affinities compared to the co-crystallized ligand and standard antibiotics like ceftaroline. Uvarinol exhibited the highest binding affinity at both sites, with a docking score of −14.94 kcal/mol and a predicted inhibition constant (Ki) of 0.01 nM. Molecular dynamics simulations further confirmed the robust stability of Uvarinol and Dichamanetin, as indicated by consistently lower RMSD values relative to the co-crystallized ligand. Pharmacokinetic predictions revealed favorable drug-likeness and low toxicity, although Uvarinol showed limited gastrointestinal absorption. Conclusions: Uvarinol and Dichamanetin show promise as dual-site PBP2a inhibitors, offering a novel strategy to combat MRSA resistance. Their structural and pharmacokinetic properties make them viable candidates for further development, though experimental validation and formulation optimization are necessary to overcome bioavailability challenges.
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- Polycystic ovarian syndrome (PCOS) is a complex reproductive disorder involving dysfunction across multiple hormonal pathways. Current pharmaceutical treatments use a simplistic single-target approach and overlook molecular interactions. This study provides a novel computational perspective revealing the promising potential of the medicinal fruit Annona muricata to target multiple receptors and modulate interconnected hormonal pathways implicated in PCOS. Molecular modeling and evaluations were done on three protein receptors involved in hormonal imbalance. The proteins were taken from the RCSB Protein Data Bank with IDs 1A28, 2AM9, and 3RUK. Over 50% of phytochemicals from Annona muricata were predicted to have binding affinities comparable to reference compounds. Docking and multi-parameter modeling using AutoDock Tools ranked the ligands, identified multi-target active compounds across all three receptors, and analyzed ligand interactions for the multiplex selected two compounds. The ADMETox properties of these phytochemicals were also analyzed. The results demonstrated various ligands with remarkable binding affinities for progesterone, androgen, and abiraterone receptor architectures matching or exceeding native standards, implying possible efficacy for coordinately modulating these interconnected hormonal sites. Detailed structural mapping of emodin and coclaurin uncovered conserved non-covalent interaction patterns, notably hydrogen bonding networks, facilitating the ligands’ competitive receptivity and deep projection into dysfunctionally upregulated pockets. The in-silico modeling provides early proof of concept that the herbal remedy A. muricata could inspire advanced "green" therapeutics for PCOS through multiplex modulation of interconnected hormonal receptors.
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