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Understanding Kinase Selectivity Through Energetic Analysis of Binding Site Waters
Author(s) -
Robinson Daniel D.,
Sherman Woody,
Farid Ramy
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200900501
Subject(s) - selectivity , kinase , chemistry , rational design , small molecule , enzyme , computational biology , binding site , biochemistry , syk , biophysics , biology , tyrosine kinase , signal transduction , genetics , catalysis
Abstract 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.