Understanding Kinase Selectivity Through Energetic Analysis of Binding Site Waters

被引：108

作者：

Robinson, Daniel D. ^{[2
]}

Sherman, Woody ^{[1
]}

Farid, Ramy ^{[1
]}

机构：

[1] Schrodinger Inc, New York, NY 10036 USA

[2] Schrodinger Inc, Surrey GU16 7ER, England

来源：

CHEMMEDCHEM | 2010年 / 5卷 / 04期

关键词：

entropy; kinases; selectivity; thermodynamics; WaterMap; INHOMOGENEOUS FLUID APPROACH; THERMODYNAMIC INTEGRATION; SOLVATION THERMODYNAMICS; MOLECULAR-MECHANICS; TYROSINE KINASE; FORCE-FIELD; INHIBITORS; SPECIFICITY; DISCOVERY; SIMULATIONS;

D O I：

10.1002/cmdc.200900501

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 lacation 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 prdeictions across the range of kinases studied here suggest that this methodology could be generally applicable for predicting selectivity profiles in realted targets.

引用

页码：618 / 627

页数：10

共 70 条

[1] Role of the active-site solvent in the thermodynamics of factor Xa ligand binding [J].