Exploration of benzhydrol analogues of 1'-acetoxychavicol acetate as potential inhibitors of sdrE adhesion protein in Staphylococcus aureus: Antimicrobial activity and multi-computational analysis.

Staphylococcus aureus, a Gram-positive bacterium, is known for causing serious infections such as bloodstream infections, pneumonia, and bone and joint infections. Recent research highlights the potential of 1'-Acetoxychavicol Acetate (ACA) and its derivatives in inhibiting S. aureus. However, the precise molecular targets of these compounds remain unclear. This study explores benzhydrol analogues based on ACA (3b, 3e, and 3 f) as potential inhibitors of the adhesion protein sdrE in S. aureus, employing both in vitro and computational methods. The inhibitory potential of these ligands against S. aureus was evaluated, while docking, MD simulations, PLIP, PCA, FEL, and DFT calculations were used to characterize their binding with sdrE. The well diffusion assay revealed that analogue 3e moderately inhibits S. aureus. Docking studies suggest that the serine-aspartate repeat-containing protein E (sdrE) in S. aureus is the likely target. PLIP analysis showed stable binding interactions of 3b, 3e, and 3 f with key sdrE residues crucial for host cell adhesion, compared to ciprofloxacin. Among them, 3b and 3e displayed strong binding affinities (-22 kcal/mol and -12 kcal/mol) with sdrE residues involved in complement regulatory protein factor H (fH) binding. Notably, 3e's binding to sdrE significantly reduced the binding affinity of factor H by nearly sixfold. PCA and FEL analyses revealed complex stability and flexibility, while DFT calculations confirmed that 3e's exhibits an optimal balance of reactivity and stability. These findings highlight the potential of ACA-based benzhydrol analogues in interacting with the adhesion protein sdrE, supporting the development of innovative inhibitors for combating S. aureus infections.