title: Exploration of type II binding mode: A privileged approach for kinase inhibitor focused drug discovery?
abstract: The ATP site of kinases displays remarkable conformational flexibility when accommodating chemically diverse small molecule inhibitors. The so-called activation segment, whose conformation controls catalytic activity and access to the substrate binding pocket, can undergo a large conformational change with the active state assuming a 'DFG-in' and an inactive state assuming a 'DFG-out' conformation. Compounds that preferentially bind to the DFG-out conformation are typically called 'type II' inhibitors in contrast to 'type I' inhibitors that bind to the DFG-in conformation. This review surveys the large number of type II inhibitors that have been developed and provides an analysis of their crystallographically determined binding modes. Using a small library of type II inhibitors, we demonstrate that more than 200 kinases can be targeted, suggesting that type II inhibitors may not be intrinsically more selective than type I inhibitors.
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, P.O. Box 1110, Hefei, Anhui 230031, P. R. China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhao
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D000818:Animals; D055808:Drug Discovery; D006801:Humans; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D011494:Protein Kinases
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