Type-II kinase inhibitor docking, screening, and profiling using modified structures of active kinase states.

ABSTRACT: Type-II kinase inhibitors represent a class of chemicals that trap their target kinases in an inactive, so-called DFG-out state, occupying a hydrophobic pocket adjacent to the ATP binding site. These compounds are often more specific than those that target active DFG-in kinase conformations. Unfortunately, the discovery of novel type-II scaffolds presents a considerable challenge, partially because the lack of compatible kinase structures makes structure-based methods inapplicable. We present a computational protocol for converting multiple available DFG-in structures of various kinases (approximately 70% of mammalian structural kinome) into accurate and specific models of their type-II bound state. The models, described as deletion-of-loop Asp-Phe-Gly-in (DOLPHIN) kinase models, demonstra

SUBMITTER: Kufareva I 

PROVIDER: S-EPMC2669721 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature