Computational identification of marine-derived therapeutic leads targeting the acyl-homoserine-lactone synthase (AHL) in drug-resistant Acinetobacter baumannii (Strain AYE).

Antimicrobial resistance is posing a major threat to public health, thus contributing to a surge in treatment failure, prolonged infections, and rising mortality. In the present study, a multi-tier virtual screening approach was employed to identify marine-derived leads targeting the acyl-homoserine-lactone synthase (AHL), a promising drug target in the ESKAPE pathogen Acinetobacter baumannii (strain AYE). Using a structurally validated AHL model for docking-based virtual screening of the CMNDPD database, four marine hit molecules, namely, CMNPD20931, CMNPD28507, CMNPD25748, and CMNPD15724, were selected based on their high docking scores (< - 8 kcal/mol) and binding energies (< - 30 kcal/mol) obtained from MMGBSA analysis and their favorable molecular interaction profiles. Pharmacokinetic screening further revealed their favorable ADMET properties, with no Lipinski rule of five (RO5) violations and acceptable toxicity profiles based on ProTox-3.0 predictions. The favorable electronic structures and corresponding HOMO and LUMO occupied regions of the hit molecules were confirmed through density functional theory (DFT) calculations. Finally, a 500 ns molecular dynamics simulation (MDS) demonstrated the structural stability of the AHL synthase upon binding with the selected CMNPD hits, supported by RMSD, RMSF, Rg, SASA, and hydrogen-bond analyses. Principal component analysis (PCA) revealed restricted phase-space motions in the ligand-bound complexes compared to the apo state. Free energy landscape (FEL) mapping based on the Gibbs free energy estimation showed the presence of distinct minima, indicating the thermodynamic stability of the complexes. Additionally, the variations in the secondary structure induced by the ligand binding were elucidated using DSSP analysis. Overall, the identified marine-derived compounds demonstrated strong binding activity and favourable pharmacokinetics against AHL synthase of Acinetobacter baumannii, suggesting their potential as promising candidates to combat drug-resistant infection. Future studies will focus on experimental validation through in vitro enzyme inhibition assays to confirm their therapeutic potential.