Abstract

Recent years have seen an explosion in the number of publicly available x-ray crystal structures of protein kinases. These structures have provided a wealth of information on the regulatory mechanisms, conformational plasticity and drugability of this important family of enzymes. Drawing upon structural information, new insights into the development of protein kinase inhibitors are discussed including de-novo design, molecular templates for ATP competitive inhibitors and alternative mechanisms of inhibition. The highly conserved nature of the ATP binding site is of central concern to drug development and the concept of a selectivity profile has arisen with structure-based design emerging as a key tool for addressing the challenges of specificity. In addition, protein-ligand complexes, where the enzyme is in an inactive conformation, signify an alternate approach to protein kinase inhibition. The belief that an inactive kinase presents a less conserved target is reviewed using observations on the structural changes occurring during protein kinase regulation.

Keywords: x-ray crystal structure, protein kinase, atp-binding site, inhibitor