Integrated Structure-Based Virtual Screening and Molecular Dynamics Simulations Identify Marine Natural Products as Potential Inhibitors of AmvR from Acinetobacter baumannii

Antimicrobial resistance (AMR) is an emerging global health concern that demands the identification of novel drug targets and bioactive molecules to combat resistant bacterial pathogens. In the present study, AmvR, a TetR family transcriptional regulator, was studied as a putative potential drug target because of its critical role in bacterial adaptation and associated antimicrobial resistance mechanisms. A structure-based virtual screening approach (SBVS) was used to identify new inhibitors derived from marine sources available in the Comprehensive Marine Natural Products Database (CMNPD) and the Seaweed Metabolite Database (SWMD). The docking protocol was first validated using spermidine, the co-crystallized ligand (RMSD = 0.12 Å), after which approximately 32,200 marine natural products (MNPs) were screened against the AmvR binding site. Four MNPs (CMNPD9680, CMNPD23795, CMNPD5249, and SWMD-BS008) identified as the top-ranked candidates based on their docking score (ranging from −11.4 to −20.3 kcal/mol) and docking-stage MMGBSA binding energy estimates (ranging from −89.7 to −104.4 kcal/mol), compared with the control ligand. Pharmacokinetics and toxicity analyses indicated favorable drug-like and safety profiles for the selected MNPs. The structural stability of apo AmvR and the ligand-bound complexes was further evaluated through 500 ns molecular dynamics (MD) simulations. Analyses of RMSD, RMSF, Rg, SASA, hydrogen-bond dynamics, post-dynamics MM/PBSA binding free energies, principal component analysis (PCA), free energy landscape (FEL) mapping, and DSSP-based secondary structure evaluation consistently demonstrated the stability of the protein–ligand interactions throughout the simulation period. Among the identified MNPs, CMNPD9680 exhibited the highest binding affinity, the most favorable docking-stage MM/GBSA binding free energy, and a stable interaction network within the AmvR binding pocket. The structural similarity analysis based on Morgan fingerprints revealed that the shortlisted marine compounds have conserved features in common with experimentally validated antibacterial compounds against Acinetobacter baumannii, making them prospective antibacterial leads. Overall, these findings demonstrate the potential of marine natural products as promising AmvR inhibitors and identify CMNPD9680 as a promising computational candidate for further experimental investigation against A. baumannii.