Computer-Aided Discovery of Potential Acinetobacter baumannii AdeB Inhibitors through Structure-Based Virtual Screening

Introduction: Drug resistance in Acinetobacter baumannii is mediated by multiple mechanisms, including multidrug efflux pumps. Among these, the AdeABC resistance-nodulation-division efflux system is one of the principal determinants, with AdeB serving as the inner membrane transporter responsible for substrate recognition and the active extrusion of structurally diverse antibacterial agents.

Objective: To identify potential inhibitors of the AdeB efflux transporter through a computer-aided drug discovery strategy integrating structure-based virtual screening and molecular docking, thereby prioritizing candidates for subsequent QSAR analysis, molecular dynamics simulations, and experimental validation.

Materials and Methods: The crystallographic structure of the AdeB efflux transporter (PDB ID: 7KGG) was prepared by reconstructing missing amino acid residues using SWISS-MODEL. A focused library of 159 compounds was retrieved from ChEMBL based on chemical similarity to previously reported AdeB inhibitors, then, a structure-based virtual screening was directed toward different binding pockets using molecular docking in AutoDock4. The resulting dataset was organized for subsequent QSAR analysis and molecular dynamics simulations.

Results: Among the highest-ranked ligands, an imidazoline-based arylsulfonamide derivative exhibited the most favorable binding free energy of −10.25 kcal/mol, followed by a hydantoin derivative with −9.98 kcal/mol, and a diaryl diamide derivative with −9.46 kcal/mol. All three ligands were predicted to bind within the distal drug-binding pocket of AdeB, a region recognized as the primary binding site for most experimentally characterized AdeB inhibitors.

Conclusion: These findings enabled the prioritization of chemically diverse ligands targeting the AdeB distal drug-binding pocket, providing a computational framework for subsequent QSAR analysis, molecular dynamics simulations, and experimental validation.