Evaluation of a focused virtual library of heterobifunctional ligands for Clostridium difficiletoxins

A focused library of virtual heterobifunctional ligands was generated in silicoand a set of ligands with recombined fragments was synthesized and evaluated for binding to Clostridium difficiletoxins. The position of the trisaccharide fragment was used as a reference for filtering docked poses during...

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Bibliographic Details
Published in:Organic & biomolecular chemistry 2014-12, Vol.13 (1), p.283-298
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: Article
Language:English
Subjects:
Clostridium
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Summary:A focused library of virtual heterobifunctional ligands was generated in silicoand a set of ligands with recombined fragments was synthesized and evaluated for binding to Clostridium difficiletoxins. 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 silicoscreening of synthetically feasible compounds and lays the groundwork for future efforts in development of composite bifunctional ligands for large clostridial toxins.
ISSN:1477-0520
1477-0539
DOI:10.1039/c4ob01838a