Exploration of Type II Binding Mode: A Privileged Approach for Kinase Inhibitor Focused Drug Discovery?
Citations Over TimeTop 1% of 2014 papers
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.
Related Papers
- → Target-Oriented and Diversity-Oriented Organic Synthesis in Drug Discovery(2000)2,550 cited
- → Antibody-enabled small-molecule drug discovery(2012)79 cited
- → Multi‐site substrate binding and interplay in barley α‐amylase 1(2008)24 cited
- [Active site of trypsin and chymotrypsin; catalytic site and substrate binding site].(1970)
- → Current Status and Strategy of Middle-Molecule Drug Discovery(2022)