In silico study to Identify New Inhibitors of Staphylococcus aureus (S. aureus) Sortase A

Subject Areas : bioinformatics

hassan sahebjamee ^{1 *} , Mehr Ali Mahmood Janlou ²

1 - Department of Biophysics, School of Biological Science, Varamin-Pishva Branch, Islamic Azad University, Varamin,Iran
2 - Department of Biology, Faculty of Biological Sciences, Gorgan Branch , Islamic Azad University, Gorgan, Iran

Received: 2024-01-06 Accepted : 2024-03-02 Published : 2025-01-08

Keywords: Srt A inhibitors, Staphylococcus aureus, Molecular docking, Molecular dynamics simulation,

Abstract :

Introduction: Inhibition of key enzymes in bacteria that exert low evolutionary pressure can be a drug development strategy for bacterial antibiotic resistance. Sortase A (Srt A) is a transpeptidase that is widely used in site-specific protein modification. This enzyme has a key function in the interactions between Staphylococcus aureus and the host and has been considered a promising target for the drug development of resistant bacteria. To date, some Srt A inhibitors have been discovered most of them are derived from flavonoid compounds, like myricetin. Aim: Since computational methods for monitoring the behavior of biomolecules at the microscopic level are more accurate and cost-effective, therefore, in this research, our goal is to use computational methods to find similar molecules but with higher binding and inhibitory effect than myricetin. Materials and Methods: In this study, we used computational methods such as structure-based virtual screening, molecular docking, MM-PBSA approach, and MD simulation. A molecular docking approach was used to understand protein-ligand interactions and inhibition constants in terms of affinity. MD simulation technique was used to monitor the conformational changes of Srt A enzyme. After the MD simulation studies, the MM-PBSA approach was used to interpret the binding free energy. Results: First, Chemspider's chemical library was screened by the "Similarity search" method, in which myricetin was placed as a reference molecule. The second stage of screening was done using PyRx software, so that the top 10 compounds were carefully selected based on their inhibitory potential from the set of ligands obtained from the previous stage. These compounds were subjected to Autodock4.2 for molecular docking. As a result, it was observed that compound-73945561 has a higher inhibitory effect than myrsteine. To investigate the stability and efficiency of ligand binding mode, free Srt A, its complexes with myrsteine and the best selected compound were subjected to 50s molecular dynamics simulation. MD simulation results showed that compound-73945561 had better binding profiles and interactions than myrsteine as a reference inhibitor, and steadily unstable behavior was observed in the docking complex. Conclusion: Overall, compound-73945561 may serve as a new inhibitor or provide a scaffold for further optimization toward the design of more potent SortA inhibitors. The development of such inhibitors would be an essential strategy against resistant bacteria.