Comparison of inhibitor binding to various kinases. Free

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An increasing number of protein kinases are being identified as potential targets for therapeutic intervention in oncology. Although in some cases inhibition of kinase activity is achieved through small molecule binding to regulatory domains, the majority of drug discovery programs are aimed at producing ATP binding site competitive ligands. There are many thousands of proteins that bind adenine in cells, so a major challenge is to introduce the appropriate spectrum of selectivity into the compounds to achieve the desired therapeutic effect. We have determined the structures of complexes between a number of known kinase inhibitors binding to the catalytic domains of various protein kinases. The proteins studied include potential oncology targets as well as kinases chosen as key selectivity markers. For some inhibitors, the binding affinity for a particular kinase is too weak to generate a structure, so models of possible binding modes have been constructed using a combination of molecular docking and modelling calculations. The resulting structures provide valuable insights into the detailed molecular basis for the differential affinity of inhibitors for particular classes of protein kinase. This detailed understanding is proving invaluable in detailed structure-based design of compounds with appropriate selectivity and affinity profiles as inhibitors of kinases such as CHK1, CDK2 and PDK1. In addition, the structures provide guidance on how to modify compounds to achieve the necessary drug-like physico-chemical and ADME properties.