Computational Drug Repurposing Targeting LuxS-Mediated Quorum Sensing in Fusobacterium nucleatum: A Virtual Screening and Molecular Dynamics Approach

Abstract Fusobacterium nucleatum is an anaerobic bacterium strongly associated with the development and progression of colorectal cancer (CRC). Its pathogenic mechanisms involve the LuxS/AI-2 quorum sensing (QS) system, which regulates biofilm formation, virulence factor expression, and host immune evasion. Targeting LuxS represents a promising anti-virulence strategy that could disrupt bacterial communication without inducing selective pressure for antibiotic resistance. In this study, we employed a computational drug repurposing pipeline to identify FDA-approved drugs capable of inhibiting the LuxS enzyme in F. nucleatum. We performed structure-based virtual screening of 9,466 compounds from DrugBank using AutoDock Vina against the AlphaFold-predicted LuxS structure (UniProt: A0A133NIU3). From 1,082 initial hits (binding energy ≤ − 7.0 kcal/mol), we applied ADMET filtering and composite scoring to select the top 5 candidates. Molecular dynamics simulations (10 ns each) using OpenMM with the AMBER14 force field confirmed the stability of all five protein–ligand complexes (RMSD < 2.0 Å). The most promising candidates include Tubocurarine (ΔG = −16.97 kcal/mol, RMSD = 1.87 Å), Docetaxel (ΔG = −13.22 kcal/mol, RMSD = 1.81 Å), Metyrosine (ΔG = −13.78 kcal/mol, RMSD = 1.97 Å), and Ergometrine (ΔG = −13.22 kcal/mol, RMSD = 1.92 Å). These results constitute an exploratory computational basis that requires subsequent experimental validation through in vitro and in vivo assays, and provide candidates for testing as anti-quorum sensing agents against F. nucleatum, with potential implications for CRC prevention and treatment. Competing Interest Statement The authors have declared no competing interest.