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 2021-4: 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

· "Potency-Enhancing Mutations of Gating Modifier Toxins for the Voltage-Gated Sodium Channel NaV1.7 Can Be Predicted Using Accurate Free-Energy Calculations"

Katz, D.; Sindhikara, D.; DiMattia, M.; Leffler, A.E., Toxins, 2021, 13(3), 193

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· "Calculating Water Thermodynamics in the Binding Site of Proteins – Applications of WaterMap to Drug Discovery"

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· "Accelerating Drug Discovery Through Tight Integration of Expert Molecular Design and Predictive Scoring"

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· "Predicting Binding Affinities for GPCR Ligands Using Free-Energy Perturbation"

Lenselink, E.B.; Louvel, J.; Forti, A.F.; van Veldhoven, J.P.D.; de Vries, H.; Mulder-Krieger, T.; McRobb, F.M.; Negri, A.; Goose, J.; Abel, R.; van Vlijmen, H.W.T.; Wang, L.; Harder, E.; Sherman, W.; IJzerman, A.P.; Beuming, T., ACS Omega, 2016, 1, 293-304

· "Chemical Basis for the Recognition of Trimethyllysine by Epigenetic Reader Proteins"

Kamps, J.J.A.G.; Huang, J.; Poater, J.; Xu, C.; Pieters, B.J.G.E.; Dong, A.; Min, M.; Sherman, W.; Beuming, T.; Bickelhaupt, F.M.; Li, H.; Mecinović, J., Nat. Commun., 2015, 6, doi:10.1038/ncomms9911

· "Interactions Between Hofmeister Anions and the Binding Pocket of a Protein"

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· "Optimization of Potent DFG-in Inhibitors of Platelet Derived Growth Factor Receptorβ (PDGF-Rβ) Guided by Water Thermodynamics"

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· "Synthesis, biological evaluation, hydration site thermodynamics, and chemical reactivity analysis of α-keto substituted peptidomimetics for the inhibition of Plasmodium falciparum"

Weldon, D.J.; Shah, F; Chittiboyina, A.G.; Sheri, A.; Chada, R.R.; Gut, J.; Rosenthal, P.J.; Shivakumar, D.; Sherman, W.; Desai, P.; Jung, J.C.; Avery, M.A., Bioorg. Med. Chem. Lett., 2014, 24(5), 1274-1279

· "Water Networks Contribute to Enthalpy/Entropy Compensation in Protein–Ligand Binding"

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· "Novel inverse binding mode of indirubin derivatives yields improved selectivity for DYRK kinases"

Myrianthopoulos, V.; Kritsanida, M.; Gaboriaud-Kolar, N.; Magiatis, P.; Ferandin, Y.; Durieu, E.; Lozach, O.; Cappel, D.; Soundararajan, M.; Filippakopoulos, P.; Sherman, W.; Knapp, S.; Meijer, L.; Mikros, E.; Skaltsounis, A.L., ACS Med Chem Lett, 2013, 4(1), 22-26

· "The Translocation Kinetics of Antibiotics Through Porin OmpC: Insights from Structure-Based Solvation Mapping using WaterMap"

Tran, Q.T.; Williams, S.; Farid, R.; Erdemli, G.; Pearlstein, R., Proteins, 2013, 81(2), 291-299

· "The Binding of Benzoarylsulfonamide Ligands to Human Carbonic Anhydrase is Insensitive to Formal Fluorination of the Ligand"

Lockett M.R.; Lange H.; Breiten B.; Heroux A.; Sherman W.; Rappoport D.; Yau P.O.; Snyder P.W.; Whitesides G.M., Angew. Chem. Int. Ed., 2013, 52(30), 7714-7717

· "Contributions of water transfer energy to protein-ligand association and dissociation barriers: WaterMap analysis of a series of p38α MAP kinase inhibitors"

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"Spirocyclic sulfamides as β-secretase 1 (BACE-1) inhibitors for the treatment of Alzheimer's disease: Utilization of structure based drug design, WaterMap, and CNS penetration studies to identify centrally efficacious inhibitors"

Brodney, M. A.; Barreiro, G.; Ogilvie, K.; Hajos-Korcsok, E.; Murray, J.; Vajdos, F.; Ambroise, C.; Christoffersen, C.; Fisher, K.; Lanyon, L.; Liu, J.; Nolan, C. E.; Withka, J. M.; Borzilleri, K. A.; Efremov, I.; Oborski, C. E.; Varghese, A.; O'Neill, B, J. Med. Chem., 2012, 55, 9224-39

· "Computer-aided drug design of falcipain inhibitors: Virtual screening, structure-activity relationships, hydration site thermodynamics, and reactivity analysis"

Shah, F.; Jiri, G.; Legac, J.; Shivakumar, D.; Sherman, W.; Rosenthal, P.J.; Avery, M., J. Chem. Inf. Model., 2012, 52(3), 696-710

· "Contribution of explicit solvent effects to the binding affinity of small-molecule inhibitors in blood coagulation factor serine proteases"

Abel, R.; Salam, N.K.; Shelley, J.; Farid, R.; Friesner, R.A.; Sherman, W. , Chem Med Chem , 2011, 6, 1049-1066

· "Mechanism of the hydrophobic effect in the biomolecular recognition of arylsulfonamides by carbonic anhydrase"

Snyder. P.W.; Mecinovic, J.; Moustakas, D.; Thomas, S, III.; Harder, M.l.; Mack, E.; Lockett, M.; Héroux, A.; Sherman, W.; Whitesides, G., PNAS, 2011, 108, 17889-17894

· "Thermodynamic analysis of water molecules at the surface of proteins and applications to binding site prediction and characterization"

Beuming, T.; Che, Y.; Abel, R.; Kim, B.; Shanmugasundaram, V.; Sherman, W., Proteins, 2011, 80, 871-83

"Addressing limitations with the MM-GB/SA scoring procedure using the WaterMap method and free energy perturbation calculations"

Guimarães, C. R.; Mathiowetz, A. M. , J. Chem. Inf. Model., 2010, 50, 547-559

· "A Displaced-Solvent Functional Analysis of Model Hydrophobic Enclosures"

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· "Understanding kinase selectivity through energetic analysis of binding site waters"

Robinson, D. D.; Sherman, W.; Farid, R., Chem. Med. Chem., 2010, 5, 618– 627

· "New hypotheses about the structure–function of proprotein convertase subtilisin/kexin type 9: Analysis of the epidermal growth factor-like repeat A docking site using WaterMap"

Pearlstein, R. A.; Hu, Q. Y.; Zhou, J.; Yowe, D.; Levell, J.; Dale, B.; Kaushik, V. K.; Daniels, D.; Hanrahan, S.; Sherman, W.; Abel, R. , Proteins, 2010, 78, 2571–2586

· "Hydration site thermodynamics explain SARs for Triazolylpurines Analogues Binding to the A2A Receptor"

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· "High-energy water sites determine peptide binding affinity and specificity of PDZ domains"

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· "The role of the active site solvent in the thermodynamics of factor Xa-ligand binding"

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Young, T.; Abel, R.; Kim, B.; Berne, B.J.; Friesner, R.A., Proc. Natl. Acad. Sci. U S A., 2007, 104, 808-813
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