In silico screening, molecular dynamic simulation, and pharmacokinetic studies of new Schiff base derivatives from 2-(3-benzoylphenyl) propionic acid as tyrosyl-tRNA synthetase inhibitor

Abstract

Bacterial resistance is a major problem in hospitals and the community. Thus, much antibacterial research has focused on discovering new chemical agents and bacterial targets. Computational and structure-based design methods are used for the improvement of drug discovery. This work developed new Schiff base compounds from 2-(3-benzoylphenyl) propionic acid. The unique compounds were categorized as S and S(1-6). They were examined in silico for antibacterial activity on the tyrosyl-tRNA synthetase enzyme. Dynamic simulation and pharmacokinetic studies were also studied theoretically. In silico, experiments, including SwissADME studies, are utilized to predict the pharmacokinetics of newly designed compounds. While the docking studies done using GOLD Suite (v. 2021.3.0) software showed the binding of compounds with the enzyme tyrosyl-tRNA synthetase, finally, dynamic simulation studies of compound [S2] using the Desmond modules of the Schrodinger 2023 software. Since all compounds meet Lipinski's rule requirements, the new agents are expected to be given orally. Docking experiments showed that compound [S2] bound to tyrosyl-tRNA synthetase had the greatest PLP fitness value (89.02) compared to the reference ligand (79.71). Simulations of the compound [S2] with the enzyme pocket revealed stable variations with RMSD values below 3Å during the simulation period. Based on docking, compound [S2] is deemed a promising agent as a tyrosyl-tRNA synthetase inhibitor, with stable variations during dynamic simulation and RMSD and RMSF values within the normal range.