Abstract
BACKGROUND: Enterococcus faecalis, a frequent cause of hospital-acquired infections such as urinary tract infections, bacteremia, endocarditis, and wound infections, is a key pathogen in persistent endodontic infections due to its resistance to conventional treatments and ability to adapt to environmental stressors. New therapeutic approaches are essential to address these challenges, particularly as antibiotic resistance rises. OBJECTIVE: The objective of this study was to systematically review in silico methodologies targeting E. faecalis proteins for identifying novel therapeutic strategies in the treatment of endodontic infections. METHODS: A comprehensive literature search (PROSPERO CRD42024610795) was conducted using PubMed, Google Scholar, and the Cochrane Library. Studies employing computer-aided drug design methods for E. faecalis protein targets were included. Molecular docking tools such as AutoDock Vina, Glide XP, and SwissDock were analyzed for their effectiveness in screening ligands and identifying promising inhibitors. In vitro validations of in silico findings were also reviewed. RESULTS: Eleven studies met the inclusion criteria. Key protein targets included Sortase A, MurA, cyclic di-AMP synthetase, and quorum-sensing regulators. Promising inhibitors such as pinocembrin, 24-propylcholesterol, and embelin were identified, with potential to disrupt biofilm formation, quorum sensing, and bacterial metabolism. While most studies confirmed findings with in vitro assays, variability in ligand preparation and docking methodologies highlighted the need for standardization. CONCLUSION: In silico approaches demonstrate substantial potential for addressing E. faecalis-associated infections by enabling efficient screening of therapeutic candidates. Integration of computational and experimental methods accelerates drug discovery, but further in vivo validation is necessary to confirm clinical efficacy and application.