Evaluation of a focused virtual library of heterobifunctional ligands for Clostridium difficile toxins. Issue 1 (4th November 2014)

• Record Type: Journal Article
• 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.
• Is Part Of: Organic & biomolecular chemistry. Volume 13:Issue 1(2015)
• Page Start: 283
• Page End: 298
• Publication Date: 2014-11-04
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/c4ob01838a
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : Higher activity glycopeptoid ligands for two large Clostridium difficile toxins TcdA and TcdB were discovered via modular fragment-based design and virtual screening. 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.