title: 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, 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.
authors.affiliation: The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Kufareva
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D030562:Databases, Protein; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D017353:Gene Deletion; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015233:Models, Statistical; D008968:Molecular Conformation; D010770:Phosphotransferases / Q000737:chemistry*; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D008024:Ligands; D011506:Proteins; D000255:Adenosine Triphosphate; D010770:Phosphotransferases