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J Med Chem. 2008 Dec 25;51(24):7921-32. doi: 10.1021/jm8010299.

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

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1
The Scripps Research Institute, La Jolla, CA 92037, USA.

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, demonstrate exceptional performance in various inhibitor discovery applications, including compound pose prediction, screening, and in silico activity profiling. Given the abundance of the DFG-in structures, the presented approach opens possibilities for kinome-wide discovery of specific molecules targeting inactive kinase states.

PMID:
19053777
PMCID:
PMC2669721
DOI:
10.1021/jm8010299
[Indexed for MEDLINE]
Free PMC Article
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