Structure-Based Virtual Screening of Small Molecules: An In Silico Strategy to Block Gelatinase in Enterococcus faecalis.

Enterococcus faecalis, a Gram-positive opportunistic pathogen, causes severe hospital-acquired infections and exhibits high antibiotic resistance due to biofilm formation. Gelatinase (GelE), a key zinc-dependent protease regulated by the Fsr system, plays a major role in biofilm maturation, tissue damage, and immune evasion. This study employed structure-based drug design to identify small-molecule inhibitors of GelE using the AlphaFold-predicted structure. Molecular docking, analog screening, and ADMET profiling revealed RS-130830 as a potent inhibitor with a binding affinity of –8.7 kcal/mol, high gastrointestinal absorption, and compliance with Lipinski’s Rule of Five, without major toxicity concerns. These findings highlight RS-130830 as a promising anti-virulence candidate and demonstrate the potential of in silico approaches for developing novel therapeutics against Enterococcus faecalis.