Evaluation of a focused virtual library of heterobifunctional ligands for Clostridium difficile toxins

• Published in: Organic & biomolecular chemistry Vol. 13; no. 1; p. 283
• Main Authors: Sanhueza, Carlos A, Cartmell, Jonathan, El-Hawiet, Amr, Szpacenko, Adam, Kitova, Elena N, Daneshfar, Rambod, Klassen, John S, Lang, Dean E, Eugenio, Luiz, Ng, Kenneth K-S, Kitov, Pavel I, Bundle, David R
• Format: Journal Article
• Language: English
• Published: England 07-01-2015
• Subjects: Amino Acid Sequence; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Binding Sites; Carbohydrate Metabolism; Clostridium difficile; Combinatorial Chemistry Techniques; Computer Simulation; Crystallography, X-Ray; Ligands; Models, Molecular; Molecular Sequence Data; Protein Conformation; Small Molecule Libraries - metabolism; Toxins, Biological - chemistry; Toxins, Biological - metabolism
• ISSN: 1477-0539
• DOI: 10.1039/c4ob01838a

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.