Structure-based virtual screening of semisynthetic isocyanide-based multicomponent reactions for the identification of potencial AdeJ transporter inhibitors in Acinetobbacter baumanii

Introduction: The multidrug resistance phenomenon in Acinetobacter baumannii, is largely mediated by the tripartite constitutive AdeIJK efflux system where, the subunit AdeJ acts as a crucial polyspecific antiporter. At the same time, semisynthetic derivatives generated from natural products through isocyanide-based multicomponent reactions constitute a chemically diverse class of compounds with significant potential biological activity, however, their potential as inhibitors of the AdeJ efflux transporter has not yet been explored.

Objective: To elucidate, through a structure-based virtual screening strategy, the thermodynamic affinity and binding mode of a chemical library comprising 176 isocyanide-based multicomponent compounds targeted the AdeJ efflux transporter, aiming to identify potential molecular inhibitors or effective steric blockers.

Materials and Methods: A structure-based virtual screening strategy was performed through molecular docking studies in Autodock4, using the AdeJ structure (PDB ID: 7M4P) and 176 semisynthetic derivatives obtained through isocyanide-based multicomponent reactions. The genetic algorithm was validated through reference ligand re-docking, yielding an RMSD of 2.186 Å, followed by predictive ADMET profiling.

Results: Virtual screening showed two semisynthetic desmycosin derivatives and one semisynthetic β-amyrin derivative emerged as the most promising candidates, exhibiting binding free energies of −16.80, −16.27, and −16.22 kcal/mol, respectively establishing hydrogen bonds and aromatic π-π stacking interactions with critical residues. In silico analysis corroborated strict compliance with Veber druggability rules, suggesting pharmacological viability.

Conclusion: These findings support the potential of semisynthetic derivatives obtained through isocyanide-based multicomponent reactions as promising candidates for AdeJ efflux transporter inhibition, providing a rational basis for subsequent in vitro and in vivo validation.