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

Authors

Cedeno, K., De Leon, D., Chiari, M.

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 Angstroms). The most promising candidates include Tubocurarine (DG = -16.97 kcal/mol, RMSD = 1.87 Angstroms), Docetaxel (DG = -13.22 kcal/mol, RMSD = 1.81 Angstroms), Metyrosine (DG = -13.78 kcal/mol, RMSD = 1.97 Angstroms), and Ergometrine (DG = -13.22 kcal/mol, RMSD = 1.92 Angstroms). 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.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 22 Apr 2026.

Stats

1-terrible, 9-excellent. How would you rate this preprint? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.