Evaluation of quercetin as a potential β-lactamase CTX-M-15 inhibitor via the molecular docking, dynamics simulations, and MMGBSA

Authors: EMRAH SARIYER, AYŞEGÜL SARAL

Abstract: Antimicrobial resistance (AMR) threatens millions of people around the world and has been declared a global risk by the World Economic Forum. One of the important AMR mechanisms in Enterobacteriaceae is the production of extended-spectrum β-lactamases. The most common ESBL, CTX-M β-lactamases, is spread to the world by CTX-M-15 and CTX-M-14. Sulbactam, clavu-lanic acid, and tazobactam are first-generation β-lactamase inhibitors and avibactam is a new non-β-lactam β-lactamase inhibitor. We studied that avibactam, sulbactam, clavulanic acid, tazobactam, and quercetin natural flavonoids were docked to target protein CTX-M-15. Subsequently, the complexes were simulated using the molecular dynamics simulations method during 100 ns for determining the final binding positions of ligands. Clavulanic acid left CTX-M-15 and other ligands remained in the binding site after the simulation. The estimated binding energies were calculated during 100 ns simulation by the MMGBSA-MMPBSA method. The estimated free binding energies of avibactam, sulbactam, quercetin, tazobactam, and clavulanic acid were sorted as -33.61 kcal/mol, -16.04 kcal/mol, -14 kcal/mol, -12.68 kcal/mol, and -2.95 kcal/mol. As a result of both final binding positions and free binding energy calculations, Quercetin may be evaluated an alternative candidate and a more potent β-lactamases inhibitor for new antimicrobial combinations to CTX-M-15. The results obtained in silico studies are predicted to be a preliminary study for in vitro studies for quercetin and similar bioactive natural compounds. These studies are notable for the discovery of natural compounds that can be used in the treatment of infections caused by β-lactamase-producing pathogens.

Keywords: β-lactamases, antibiotic resistance, quercetin, molecular docking, molecular dynamics simulations

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