A new paradigm in ligand optimization

The Advantages of Detailed Desolvation Thermodynamics

Subtle structural variations in ligands can have profound impact on binding affinity to the protein target. Often these mystifying effects can be explained by a detailed examination of the thermodynamics of binding, including the free energy changes resulting from displacing water molecules in the active site.

Mapping the locations and thermodynamic properties of water molecules that solvate protein binding sites offers rich physical insights into the properties of the pocket and quantitatively describes the hydrophobic forces driving the binding of small molecules.

Rigorous theory:
WaterMap is based on inhomogeneous solvation theory of Lazaridis and Karplus, J Phys Chem B 102, p3531, where enthalpy is taken directly from nonboded interactions and entropy is computed from a local expansion of spatial and orientational correlation functions. 

MD simulation:
Efficiently converged MD simulations are run with explicit water molecules, and resultant trajectories are analyzed to cluster hydration sites. Free energy analysis: Entropy and enthalpy are computed for each hydration site and energy terms are computed relative to bulk solvent.

Widely Applicable:
To date WaterMap has been applied to a wide range of systems including enzymes, GPCRs, bromodomains, nucleic acids, and protein-protein interfaces.

Advanced visualization:
WaterMap presents the computed results graphically for easy visualization of hydration sites, making interpretation of SAR intuitive and offers insights to possible design routes to improve potency and selectivity.

Citations and Acknowledgements

Schrödinger Release 2022-4: WaterMap, Schrödinger, LLC, New York, NY, 2021.

ö Abel, R.; Young, T.; Farid, R.; Berne, B.J.; Friesner, R.A., "Role of the active-site solvent in the thermodynamics of Factor Xa ligand binding," J. Am. Chem. Soc., 2008, 130, 2817-2831

ö Young, T.; Abel, R.; Kim, B.; Berne, B.J.; Friesner, R.A., "Motifs for molecular recognition exploiting hydrophobic enclosure in protein–ligand binding," Proc. Natl. Acad. Sci. U S A., 2007, 104, 808-813

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