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Type-II Kinase Inhibitor Docking, Screening, and Profiling Using Modified Structures of Active Kinase States
 

Summary: Type-II Kinase Inhibitor Docking, Screening, and Profiling Using
Modified Structures of Active Kinase States
Irina Kufareva1 and Ruben Abagyan1,2,*
1The Scripps Research Institute, La Jolla, CA
2Molsoft, LLC, La Jolla, CA
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 targeting active, DFG-in, kinase conformations.
Unfortunately, the discovery of novel type-II scaffolds presents a considerable challenge, partly
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 (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.
Keywords
kinase; DFG-in; DFG-out; type-II inhibitor; imatinib; structure-based inhibitor discovery; compound

  

Source: Abagyan, Ruben - School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego

 

Collections: Biology and Medicine