title: Understanding kinase selectivity through energetic analysis of binding site waters.
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.
authors.affiliation: Schrödinger Inc, Quatro House, Frimley Road, Camberley, Surrey GU16 7ER, UK.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Robinson
authors.forename: Woody
authors.initials: W
authors.lastname: Sherman
authors.forename: Ramy
authors.initials: R
authors.lastname: Farid
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry / Q000378:metabolism; D030562:Databases, Protein; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D000072377:Syk Kinase; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*; D019061:src-Family Kinases / Q000737:chemistry / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D014867:Water; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; D000072377:Syk Kinase; D019061:src-Family Kinases; D051357:Cyclin-Dependent Kinase 2