Small-molecule inhibitors binding to protein kinases. Part I: exceptions from the traditional pharmacophore approach of type I inhibition

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Abstract
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. 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. The scope of this review covers published crystal structures of protein kinases in complex with various ligands. 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.