Molecular Docking of Selected Compounds against Verona Integroncoded Metallo-Β-Lactamase (Vim) Variants of Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa is considered a serious threat to global human health as it causes nosocomial infections while exhibiting significant antibiotic resistance. Through the action of the Verona Integron-encoded Metallo-β-lactamase (VIM)-2, P. aeruginosa is now resistant to carbapanems, a class of last-resort antibiotics. Therefore, there is a need for novel drugs targeting the VIM-2. This study aimed to determine drug repurposing candidates from FDA-approved drugs, DOH-approved medicinal plants, and derivatives of gallic acid, for their potential to inhibit VIM-1, VIM-2, VIM-4, VIM-5, and VIM-7 isoforms in P. aeruginosa. For each protein target, top binders with binding energies ≤ -10.00 kcal/mol were obtained by molecular docking using AutoDock Vina, and ADMETLab was used to screen the lead compounds for adherence to Lipinski's Rule of Five and to predict their pharmacokinetic properties. Two hundred sixty-three had binding affinities ranging from -10.0 to -13.9 kcal/mol. Among these, five FDA-approved drugs, and one compound, DOH1, showed high binding affinities with three out of the five target VIM isoforms of P. aeruginosa. Pharmacophore models with four features were generated, which could be utilized to further optimize lead compounds. Moreover, ligand-protein interactions revealed that the top most frequently interacting residues for both hydrophobic interactions and hydrogen bonding had high (80-100%) and intermediate (50-79%) conservation statuses. The results indicate the potential of these compounds to inhibit multiple VIM targets associated with antimicrobial resistance and provide useful insights for the development of novel antibiotics for the effective treatment of P. aeruginosa infections.