title: Evaluation of a focused virtual library of heterobifunctional ligands for Clostridium difficile toxins.
abstract: A focused library of virtual heterobifunctional ligands was generated in silico and a set of ligands with recombined fragments was synthesized and evaluated for binding to Clostridium difficile toxins. The position of the trisaccharide fragment was used as a reference for filtering docked poses during virtual screening to match the trisaccharide ligand in a crystal structure. The peptoid, a diversity fragment probing the protein surface area adjacent to a known binding site, was generated by a multi-component Ugi reaction. Our approach combines modular fragment-based design with in silico screening of synthetically feasible compounds and lays the groundwork for future efforts in development of composite bifunctional ligands for large clostridial toxins.
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Canada. dave.bundle@ualberta.ca.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Sanhueza
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cartmell
authors.forename: Amr
authors.initials: A
authors.lastname: El-Hawiet
authors.forename: Adam
authors.initials: A
authors.lastname: Szpacenko
authors.forename: Elena N
authors.initials: EN
authors.lastname: Kitova
authors.forename: Rambod
authors.initials: R
authors.lastname: Daneshfar
authors.forename: John S
authors.initials: JS
authors.lastname: Klassen
authors.forename: Dean E
authors.initials: DE
authors.lastname: Lang
authors.forename: Luiz
authors.initials: L
authors.lastname: Eugenio
authors.forename: Kenneth K-S
authors.initials: KK
authors.lastname: Ng
authors.forename: Pavel I
authors.initials: PI
authors.lastname: Kitov
authors.forename: David R
authors.initials: DR
authors.lastname: Bundle
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D050260:Carbohydrate Metabolism; D016360:Clostridioides difficile; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D054852:Small Molecule Libraries / Q000378:metabolism*; D014118:Toxins, Biological / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D008024:Ligands; D054852:Small Molecule Libraries; D014118:Toxins, Biological