CADD approach in the development of antibacterial molecules to inhibit Gyrase B in Staphylococcus aureus

Given the growing number of drug-resistant bacteria, research into antibacterial agents is essential. As a pathogen, S. aureus is prone to rapidly acquire resistance genes. Bacterial DNA gyrase is one of the desirable targets for the development of antimicrobial agents. This enzyme catalyzes topological changes in DNA, and subunit B of this enzyme, GyrB, has ATPase activity. Therefore, if the activity of this subunit is inhibited, the necessary energy for replication and transcription of DNA is not provided. The proposed properties have made this enzyme a suitable new target for the identification of inhibitory molecules. Computer Aided Drug Design (CADD) approaches have played a very effective role in accelerating and optimizing the economic process of drug design and development. In this study, the pharmacophore modeling was used to identify potential inhibitors. In this regard, GyrB structure together with pyrazolethiazole (PDB code :۳g۷۵) was extracted from PDB database. Based on laboratory data, pharmacophore modeling was performed using Lipinski's five rules and Pharmit server. based on the pharmacophoric model, a search has been done in the ZINC database and ۳۲۹ hits were found. Virtual screening was performed using Pyrx software and ۲۰ molecules with the most favorable ΔG between -۷ to -۸.۹, were selected. Finally, the ADMET properties prediction of these molecules was performed using ADMETlab.According to the results of previous researches on the factors affecting the optimal binding to the Gyrase and other features like, druglikines, logS and toxisity, ZINC۰۰۰۰۲۳۴۳۰۷۱۹,ZINC۰۰۰۰۷۲۱۴۷۴۵۹, ZINC۰۰۰۲۶۱۳۶۵۰۸۴, ZINC۰۰۰۰۰۵۸۶۵۳۲۸ and ZINC۰۰۰۰۰۱۰۳۳۹۴۴ were introduced as hit molecules. Based on this fact that search has been done on chemical molecules database and despite the development of computational systems and the high accuracy of these methods, it is suggested that selected molecules as drug hit compounds be evaluated by laboratory approaches.

کلیدواژه ها:

Drug resistance ، Pharmacophore ، ADMET ، S.aureus ، DNA gyrase