Multistep In-Silico Pipeline for Targeting FimH Adhesin with Chalcones as Anti-Adhesion Therapeutics

Introduction: FimH, a bacterial adhesin on Uropathogenic Escherichia coli (UPEC), facilitates host cell attachment and initiates Urinary Tract Infections (UTIs). With rising antibiotic resistance, alternative therapeutics targeting bacterial adhesion are urgently needed. This study in-vestigates chalcone derivatives as potential anti-adhesive agents against FimH, aiming to inhibit bacterial colonization and reduce virulence through an in-silico approach. Methods: A total of 200 chalcone derivatives were subjected to in-silico toxicity screening using ProTox-II, followed by molecular docking using MVD 6.0 and AutoDock Vina against FimH (PDB IDs: 5AAP and 4XO8). The most promising compounds underwent structural pharmacophore mod-eling in LigandScout, pharmacokinetic profiling via SwissADME and PreADMET, and further validation through molecular dynamics simulations and MMPBSA free energy calculations. Results: Chalcones 103, 122, and 137 showed strong binding affinities, with highly negative MolDock scores surpassing native ligands. Key residues such as Gln133, Asp47, and Phe1 were identified as essential for hydrogen bonding. Pharmacokinetic profiles revealed high gastrointesti-nal absorption, BBB permeability, and compliance with major drug-likeness filters. RMSF analysis indicated 4XO8’s structural rigidity, while MMPBSA confirmed strong binding energies, particu-larly for the 4XO8-137 complex. Discussion: These findings suggest chalcone derivatives, especially Chalcone 137, demonstrate promising anti-adhesive properties, structural stability, and favourable pharmacokinetics, making them viable candidates for further drug development. Conclusion: Chalcones 103, 122, and 137, particularly the 4XO8-137 complex, exhibit strong ther-apeutic potential as non-antibiotic anti-adhesion agents against UTI-causing E. coli, warranting further experimental validation in-vitro and in-vivo.