Napthyridine-derived compounds as promising inhibitors for Staphylococcus aureus CrtM: a primer for the discovery of potential anti-Staphylococcus aureus agents

Abstract

The disease-free existence of humans is constantly under attack by a variety of infections caused by a variety of organisms including bacteria. Notable among the bacteria is Staphylococcus aureus which is an etiological organism for infections including impetigo, folliculitis, and furuncles. The response of the human immune system against this disease is often neutralized by the production of a pigment called Staphyloxanthin (STX) via a series of reactions mediated by several enzymes. Among these enzymes, dehydrosqualene synthase, also known as CrtM, has emerged as a viable drug target due to its role in mediating the first step of the pathway. Consequently, this study employs molecular modeling approaches including molecular docking, quantum mechanical calculations, and molecular dynamics (MD) simulations among others to investigate the potential of napthyridine derivatives to serve as inhibitors of the CrtM. The results of the study revealed the high binding affinities of the compounds for the target as demonstrated by their docking scores, while further subjection to screening pipeline aimed at determining their fitness for development into drugs revealed just one compound namely 6-[[1-[(2-fluorophenyl) methyl]triazol-4-yl]methoxy]-4-oxo-1H-1,5-naphthyridine-3-carboxylic acid as the compound with good drug-like, pharmacokinetics, and toxicity properties profiles. A 100 ns-long MD simulation of the complexes formed after molecular docking revealed the stable interaction of the compound with the target. Ultimately, this study can be a promising outlet to discover a weapon to fight against clinically resistant bacteria, however, further experimental studies are suggested to carry out in the wet lab, pre-clinical, and clinical levels.