Screening of prospective biofilm-inhibitory drug candidates aimed at the biofilm-associated protein (BAP) in Staphylococcus aureus: An in-silico investigation.

Staphylococcus aureus is the leading pathogen responsible for hospital- and community-acquired infections. The increasing prevalence of nosocomial infections in healthcare settings presents a significant challenge, particularly due to the strong biofilm-forming capability of clinical strains, which contributes to biofilm-mediated multidrug resistance. The biofilm-associated protein (BAP) plays a pivotal role in the initial adhesion and maturation of biofilms, significantly increasing the likelihood of failure of conventional antimicrobial therapies. Given its crucial function in biofilm formation, BAP represents a promising target for anti-biofilm drug development. A high-throughput virtual screening technique was implemented to identify potent BAP inhibitors, utilizing triple-mode docking with the Glide module of the Schrödinger Maestro suite. About 28,831 compounds from the ENAMINE-targeted antibacterial library were screened against BAP in S. aureus. Among the selected ligands, Z1430813924 and Z1738791774 exhibited the lowest binding energy, demonstrating superior docking scores alongside favorable ADME and physicochemical properties, which suggests an enhanced inhibitory potential. To validate the docking findings, a 100-ns molecular dynamics simulation was employed to assess the stability of the protein-ligand complex within a dynamic environment. The essential dynamics analysis, including free energy landscape (FEL) and principal component analysis (PCA) evaluations, affirmed the stability and efficacy of the top compounds, Z1430813924 and Z1738791774, as promising BAP inhibitors. These insights provide a strong foundation for subsequent experimental validation and the potential development of novel anti-biofilm therapeutics targeting S. aureus infections.