Identifying FmlH lectin-binding small molecules for the prevention of Escherichia coli-induced urinary tract infections using hybrid fragment-based design and molecular docking.

Nearly 50% of women are affected by urinary tract infections (UTIs) during their lifetimes. The most common agent to cause UTIs is Uropathogenic Escherichia coli (UPEC). UPEC expresses fibers known as chaperone-usher pathway pili with adhesins that specifically bind to receptors as they colonize various host tissues. UPEC uses an F9/Yde/Fml pilus, tipped with FmlH, which interacts with terminal galactoside/galactosaminoside units in glycoproteins in the epithelial cells of the bladder and kidney. The extensive use of traditional antibiotics has led to the rise of various antibiotic-resistant strains of UPEC. An alternative therapeutic approach is to use an anti-adhesion strategy mediated by competitive tight-binding FmlH inhibitors. In the current study, we have applied various computational modeling techniques, including fragment-based e-pharmacophore virtual screening, molecular docking, molecular dynamics simulations and binding free energy calculations for the design of small molecules that exhibit binding to FmlH. Our modeling protocol successfully predicted ligand moieties, such as a thiazole group, which were previously found as components of UPEC adhesin pili inhibitors, thereby validating our designed screening protocol. The screening protocol developed here could be utilized for design of ligands for other homologous protein targets. We also identified several novel galactosaminoside-containing molecules that, according to the computational modeling, are predicted to interact strongly with FmlH and hence we predict will be good FmlH inhibitors. Additionally, we have prepared and supplied a database of ∼190K small molecules obtained from virtual screening, which can serve as an excellent resource for the discovery of novel FmlH inhibitors.