Journal
EXPERT OPINION ON DRUG DISCOVERY
Volume 3, Issue 12, Pages 1409-1425Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1517/17460440802579975
Keywords
binding mode; kinase inhibitors; pharmacophore model; protein kinase; structure-based drug design; Traxler model
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Background: Protein kinases are essential enzymes propagating cellular signal transduction processes and consequently have emerged as central targets for drug discovery against a wide range of diseases with a strong historical focus on oncological disorders. A large number of high-resolution crystal structures of various ATP-competitive inhibitors in complex with their target protein kinases have been determined and present a wealth of detailed information about binding modes, inhibition mechanisms and associated structure-activity relationships of target-bound small molecules. Objective: In this first part of a two-part review, exceptions to the type I binding mode of kinase inhibitors that follow the traditional pharmacophore model are discussed, highlighting unexpected structural features. Methods: The scope of this review covers published crystal structures of protein kinases in complex with various ligands. Results: Structural parameters of both inhibitors and kinases contribute to the complexity of designing kinase inhibitors. The continued study of high-resolution structures of ligand-enzyme complexes in combination with a more dynamic understanding of accessible conformational states of the target proteins, supported by detailed kinetic studies, will in the long-term help in developing new low-molecular weight kinase inhibitors.
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