Integrated Approaches for Discovery of Staphylococcus aureus Antimicrobial Agents: Virtual Screening, Molecular Docking, Molecular Dynamics Simulations, and Density Functional Theory.

Due to the excessive use of antibiotics, Staphylococcus aureus has developed resistance to conventional antibiotics. This study primarily employs virtual screening methods to explore the binding mode, biological stability, electronic properties, and antimicrobial activity of the drugs. Lactate dehydrogenase (LDH) was chosen as the primary target, and virtual screening of approximately 3180 FDA-approved drugs was performed. On the basis of binding affinity scores, the top 12 molecules were shortlisted for further analysis through precise docking and MMGBSA calculations. Molecular docking simulations revealed that these compounds exhibit a strong affinity for the target protein 6BAZ, with Gliquidone demonstrating the highest binding affinity at -76.25 kcal/mol. The top three hit molecules were subjected to 100 ns molecular dynamics simulations, which confirmed the stability of the ligand-protein complexes through hydrophobic and hydrogen bonding interactions, corroborating the docking and MMGBSA findings. Density functional theory (B3LYP level, 6-31 + G (d, p) basis set) was applied to evaluate molecular geometry optimization and vibrational frequencies, offering valuable insights into the structure and stability of the drug molecules, which further supports their potential as lead compounds for LDH inhibition and establishes a strong basis for future drug development and optimization.