877273-27-3Relevant articles and documents
Importance of ligand bioactive conformation in the discovery of potent indole-diamide inhibitors of the hepatitis C virus NS5B
Laplante, Steven R.,Gillard, James R.,Jakalian, Araz,Aubry, Norman,Coulombe, Rene,Brochu, Christian,Tsantrizos, Youla S.,Poirier, Martin,Kukolj, George,Beaulieu, Pierre L.
supporting information; experimental part, p. 15204 - 15212 (2010/12/29)
Significant advances have led to receptor induced-fit and conformational selection models for describing bimolecular recognition, but a more comprehensive view must evolve to also include ligand shape and conformational changes. Here, we describe an example where a ligand's "structural hinge" influences potency by inducing an "L-shape" bioactive conformation, and due to its solvent exposure in the complex, reasonable conformation-activity-relationships can be qualitatively attributed. From a ligand design perspective, this feature was exploited by successful linker hopping to an alternate "structural hinge" that led to a new and promising chemical series which matched the ligand bioactive conformation and the pocket bioactive space. Using a combination of X-ray crystallography, NMR and modeling with support from binding-site resistance mutant studies and photoaffinity labeling experiments, we were able to derive inhibitor-polymerase complexes for various chemical series.
