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Repurposing of Compounds From Streptomyces Spp. As Potential Inhibitors of Aminoacyltransferase Fema: An Essential Drug Target Against Antibiotic-Resistant Staphylococcus Aureus Publisher Pubmed



N Noori Goodarzi NARJES ; B Shahbazi BEHZAD ; Ehag Khiavi Elham Haj Agha GHOLIZADEH ; K Asforooshani KHAZANI ; S Abed SAHAR ; F Badmasti FARZAD
Authors

Source: Current Computer-Aided Drug Design Published:2025


Abstract

Background: Drug-resistant Staphylococcus aureus represents a substantial healthcare challenge worldwide, and its range of available therapeutic options continues to diminish progressively. Thus, this study aimed to identify potential inhibitors against FemA, a crucial protein involved in the cell wall biosynthesis of S. aureus. Materials and Methods: The screening process involved a comprehensive structure-based virtual screening on the StreptomDB database to identify ligands with potential inhibitory effects on FemA using AutoDock Vina. The most desirable ligands with the highest binding affinity and pharmacokinetic properties were selected. Two ligands with the highest number of hydrogen bonds and hydrophobic interactions were further analyzed by molecular dynamics (MD) using the GROMACS version 2018 simulation package. Results: Six H-donor conserved residues were selected as protein active sites, including Arg-220, Tyr-38, Gln-154, Asn-73, Arg-74, and Thr-24. Through virtual screening, a total of nine compounds with the highest binding affinity to the FemA protein were identified. Frigocyclinone and C21H21N3O4 exhibited the highest binding affinity and demonstrated favorable pharmacokinetic properties. Molecular dynamics analysis of the FemA-ligand complexes further indicated desirable stability and reliability of complexes, reinforcing the potential efficacy of these ligands as inhibitors of FemA protein. Conclusion: Our findings suggest that Frigocyclinone and C21H21N3O4 are promising inhibitors of FemA in S. aureus. To further validate these computational results, experimental studies are planned to confirm the inhibitory effects of these compounds on various S. aureus strains. Combining computational screening with experimental validation contributes valuable insights to the field of drug discovery in comparison to the classical drug discovery approaches. © 2025 Elsevier B.V., All rights reserved.
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