Evaluating the ability of in silico identified hit compounds to bind Staphylococcus aureus LcpASA using steered molecular dynamics simulations.

Staphylococcus aureus is an opportunistic microorganism which can cause minor skin infections and also serious diseases, and its increasing antibiotic resistance necessitates further discovery of new targets and inhibitors for antibacterials. The transmembrane protein LcpA_SA that plays an essential role in the synthesis of cell wall in S. aureus has been identified as a potential drug target. In this study, we performed virtual screening of chemical compound libraries to establish their binding with target protein and molecular docking among other studies which led to identification of hit compounds with good binding affinity towards LcpA_SA domain and involvement of key amino acid residues in the intermolecular interactions. All molecules showed satisfactory drug-likeness properties such as ADME and non-carcinogenicity. 500 ns molecular dynamics (MD) simulations using Amber18 was performed on all molecular systems to explain the mechanism of LcpA_SA extracellular domain function and reveal potential hit molecules to bind the enzyme. Based on the post-MD data analysis; such as RMSD, RMSF, SASA, intermolecular hydrogen bonds, clustering analysis, anisotropic network model-based normal mode analysis and mechanical stiffness, and essential dynamics seven molecules were finally selected as hit compounds to bind LcpA_SA. Steered MD was employed to study the unbinding of the hit molecules.