Abstract
The ability to accurately characterize the solvation properties (water locations and thermodynamics) of biomolecules is of great importance to drug discovery. While crystallography, NMR, and other experimental techniques can assist in determining the structure of water networks in proteins and protein-ligand complexes, most water molecules are not fully resolved and accurately placed. Furthermore, understanding the energetic effects of solvation and desolvation on binding requires an analysis of the thermodynamic properties of solvent involved in the interaction between ligands and proteins. WaterMap is a molecular dynamics-based computational method that uses statistical mechanics to describe the thermodynamic properties (entropy, enthalpy, and free energy) of water molecules at the surface of proteins. This method can be used to assess the solvent contributions to ligand binding affinity and to guide lead optimization. In this review, we provide a comprehensive summary of published uses of WaterMap, including applications to lead optimization, virtual screening, selectivity analysis, ligand pose prediction, and druggability assessment.
Keywords: Water, WaterMap, Lead optimization, Thermodynamics, Solvation, Druggability, Specificity, Kinetics.
Current Topics in Medicinal Chemistry
Title:Calculating Water Thermodynamics in the Binding Site of Proteins – Applications of WaterMap to Drug Discovery
Volume: 17 Issue: 23
Author(s): Daniel Cappel, Woody Sherman and Thijs Beuming*
Affiliation:
- Schrödinger Inc., 120 West 45th Street, New York, NY 10036,United States
Keywords: Water, WaterMap, Lead optimization, Thermodynamics, Solvation, Druggability, Specificity, Kinetics.
Abstract: The ability to accurately characterize the solvation properties (water locations and thermodynamics) of biomolecules is of great importance to drug discovery. While crystallography, NMR, and other experimental techniques can assist in determining the structure of water networks in proteins and protein-ligand complexes, most water molecules are not fully resolved and accurately placed. Furthermore, understanding the energetic effects of solvation and desolvation on binding requires an analysis of the thermodynamic properties of solvent involved in the interaction between ligands and proteins. WaterMap is a molecular dynamics-based computational method that uses statistical mechanics to describe the thermodynamic properties (entropy, enthalpy, and free energy) of water molecules at the surface of proteins. This method can be used to assess the solvent contributions to ligand binding affinity and to guide lead optimization. In this review, we provide a comprehensive summary of published uses of WaterMap, including applications to lead optimization, virtual screening, selectivity analysis, ligand pose prediction, and druggability assessment.
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Cite this article as:
Cappel Daniel, Sherman Woody and Beuming Thijs *, Calculating Water Thermodynamics in the Binding Site of Proteins – Applications of WaterMap to Drug Discovery, Current Topics in Medicinal Chemistry 2017; 17 (23) . https://dx.doi.org/10.2174/1568026617666170414141452
DOI https://dx.doi.org/10.2174/1568026617666170414141452 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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