Zhao, ZhengWu, HongWang, LiLiu, YiKnapp, StefanLiu, QingsongGray, Nathanael2014-07-072014Zhao, Zheng, Hong Wu, Li Wang, Yi Liu, Stefan Knapp, Qingsong Liu, and Nathanael S. Gray. 2014. “Exploration of Type II Binding Mode: A Privileged Approach for Kinase Inhibitor Focused Drug Discovery?” ACS Chemical Biology 9 (6): 1230-1241. doi:10.1021/cb500129t. http://dx.doi.org/10.1021/cb500129t.1554-8929http://nrs.harvard.edu/urn-3:HUL.InstRepos:12406535The 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.en-USReviewsJournal Article2014-07-0710.1021/cb500129t