In silico studies for the identification of potential inhibitors of the QACE protein against antibiotic-resistant Acinetobacter baumannii

Introduction: Acinetobacter baumannii is a multidrug-resistant pathogen from the ESKAPE group, associated with nosocomial infections. Its resistance to multiple antibiotics poses a global threat. The QACE protein, an efflux pump, has been identified as a key resistance mechanism, making it a promising target for the development of new antibacterial agents.

Objective: To identify low molecular weight compounds derived from natural products with potential inhibitory activity against the QACE protein, using virtual screening and molecular docking studies.

Materials and Methods: The three-dimensional structure of QACE was retrieved from AlphaFold, followed by energy minimization and assignment of Kollman-type charges. Ligand screening was performed using the BioMX database through structural similarity analysis (Tanimoto coefficient ≥ 0.85), using ciprofloxacin as the reference compound. Selected molecules were evaluated using SwissADME to predict their pharmacokinetic properties, and three candidates with favorable profiles were chosen. Molecular docking studies were then performed using AutoDock 4 to estimate binding affinities.

Results: Voacangine was the compound with the highest structural similarity, strongest binding affinity to QACE (ΔG = -6.2 kcal/mol; Ki = 28.51 μM), and stable molecular interactions including hydrogen bonds and π-stacking. It showed favorable tissue distribution, low potential for CYP3A4 inhibition, and minimal predicted cardiotoxicity (hERG channel blockade).

Conclusion: Voacangine emerges as a promising candidate for inhibiting the QACE efflux pump in Acinetobacter baumannii. This study highlights the value of computer-aided drug design as an effective strategy in the search for new treatments against multidrug-resistant bacteria.