Quantitative structure–activity relationship modeling and docking of some synthesized bioactive oxopyrolidines against Staphylococcus aureus

Abstract

Quantitative correlations of chemical compounds' biological activity (response variables) with their molecular structures are known as QSARs (independent variables). The molecular descriptors account for a molecule's conformational, constitutional, thermodynamic, steric effects, and electronic characteristics. Molecular docking is one of the most commonly used strategies in structure-based drug design because of its ability to predict the binding-conformation of small-molecule ligands to the proper target binding site. The study of binding behaviour aids in the rational design of therapeutics at the molecular level. A series of novel bioactive oxopyrrolidine derivatives were reported to be synthesized from benzimidazole, pyrrolidinone, pyrrole, 1,2,4-triazole, thiazole, and oxadiazole with 1-(3-(1,3-thiazol-2-yl)phenyl)-5-oxopyrrolidines substituents. Consequently, oxopyrrolidines used possess thiazole ring obtained from reaction of either benzenecarbothioamide, tioureido acid or thiocarbamide with 1-(4-(bromoacetyl)phenyl)-5-oxopyrrolidine-3-carboxylic acid heterocyclic fragments. It was further compared with control Oxytetracycline in which quinoxaline containing fragment showed the more marked effect than of the used control antibiotic. Therefore, this study aimed to build a robust QSAR model to predict the anti-bacterial activity of some oxopyrolidines compounds against Staphylococcus aureus and carry out molecular docking studies between the compounds of the tyrosyltRNAsynthethase receptor. Based on the obtained values of the validation parameters, such as R2 (0.9049), R2adj (0.8789), and Q2cv(0.8365), necessary to evaluate the strength and robustness of the QSAR model, the developed QSAR model was deemed to be statistically significant. Some compounds were chosen and docked with the Staphylococcustyrosyl tRNA synthethase receptor, and the results suggest that C3, C7, C12, C17, C18, and C19 with free binding energies (FBE) −10.0 kcal/mol, −9.6 kcal/mol, −10.2 kcal/mol, −10.1 kcal/mol, −10.6 kcal/mol and −9.7 kcal/mol respectively were better than the standard tyrosyltRNAsynthethase inhibitor (Linezolid, FBE = −8.3 kcal mol−1). Furthermore, these compounds met the drug-likeness criteria and were orally bioavailable. The six compounds' modeling, docking, and drug similarity features broaden the scope of novel derivative design, manufacturing, and testing against Staphylococcus aureus.