Understanding Kinase Selectivity Through Energetic Analysis of Binding Site Waters

• Published in: ChemMedChem 2010-04, Vol.5 (4), p.618-627
• Main Authors: Robinson, Daniel D., Sherman, Woody, Farid, Ramy
• Format: Article
• Language: English
• Subjects: Binding Sites; Computer Simulation; Cyclin-Dependent Kinase 2 - chemistry; Cyclin-Dependent Kinase 2 - metabolism; Databases, Protein; entropy; Intracellular Signaling Peptides and Proteins - chemistry; Intracellular Signaling Peptides and Proteins - metabolism; kinases; Models, Molecular; Protein Binding; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinases - chemistry; Protein Kinases - metabolism; Protein-Tyrosine Kinases - chemistry; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins c-abl - chemistry; Proto-Oncogene Proteins c-abl - metabolism; selectivity; src-Family Kinases - chemistry; src-Family Kinases - metabolism; Structure-Activity Relationship; Syk Kinase; Thermodynamics; Water - chemistry; WaterMap
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.200900501

Kinases remain an important drug target class within the pharmaceutical industry; however, the rational design of kinase inhibitors is plagued by the complexity of gaining selectivity for a small number of proteins within a family of more than 500 related enzymes. Herein we show how a computational method for identifying the location and thermodynamic properties of water molecules within a protein binding site can yield insight into previously inexplicable selectivity and structure–activity relationships. Four kinase systems (Src family, Abl/c‐Kit, Syk/ZAP‐70, and CDK2/4) were investigated, and differences in predicted water molecule locations and energetics were able to explain the experimentally observed binding selectivity profiles. The successful predictions across the range of kinases studied here suggest that this methodology could be generally applicable for predicting selectivity profiles in related targets. WaterMap: A series of examples show how an understanding of the behaviour of explicit water molecules in the binding sites of various kinases can be used to explain inhibitor selectivity trends.