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Thermodynamic Insight into the Effects of Water Displacement and Rearrangement upon Ligand Modifications using Molecular Dynamics Simulations.
ChemMedChem 2018; 13(13):1325-1335C

Abstract

Computational methods, namely molecular dynamics (MD) simulations in combination with inhomogeneous fluid solvation theory (IFST) were used to retrospectively investigate various cases of ligand structure modifications that led to the displacement of binding site water molecules. Our findings are that water displacement per se is energetically unfavorable in the discussed examples, and that it is merely the fine balance between change in protein-ligand interaction energy, ligand solvation free energies, and binding site solvation free energies that determine if water displacement is favorable or not. We furthermore evaluated if we can reproduce experimental binding affinities by a computational approach combining changes in solvation free energies with changes in protein-ligand interaction energies and entropies. In two of the seven cases, this estimation led to large errors, implying that accurate predictions of relative binding free energies based on solvent thermodynamics is challenging. Nevertheless, MD simulations can provide insight regarding which water molecules can be targeted for displacement.

Authors+Show Affiliations

Molecular Modeling, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.Molecular Modeling, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29726604

Citation

Wahl, Joel, and Martin Smieško. "Thermodynamic Insight Into the Effects of Water Displacement and Rearrangement Upon Ligand Modifications Using Molecular Dynamics Simulations." ChemMedChem, vol. 13, no. 13, 2018, pp. 1325-1335.
Wahl J, Smieško M. Thermodynamic Insight into the Effects of Water Displacement and Rearrangement upon Ligand Modifications using Molecular Dynamics Simulations. ChemMedChem. 2018;13(13):1325-1335.
Wahl, J., & Smieško, M. (2018). Thermodynamic Insight into the Effects of Water Displacement and Rearrangement upon Ligand Modifications using Molecular Dynamics Simulations. ChemMedChem, 13(13), pp. 1325-1335. doi:10.1002/cmdc.201800093.
Wahl J, Smieško M. Thermodynamic Insight Into the Effects of Water Displacement and Rearrangement Upon Ligand Modifications Using Molecular Dynamics Simulations. ChemMedChem. 2018 07 6;13(13):1325-1335. PubMed PMID: 29726604.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Thermodynamic Insight into the Effects of Water Displacement and Rearrangement upon Ligand Modifications using Molecular Dynamics Simulations. AU - Wahl,Joel, AU - Smieško,Martin, Y1 - 2018/05/30/ PY - 2018/02/13/received PY - 2018/04/07/revised PY - 2018/5/5/pubmed PY - 2019/6/25/medline PY - 2018/5/5/entrez KW - binding affinity KW - inhomogeneous fluid solvation theory KW - ligand optimization KW - molecular dynamics KW - solvent displacement SP - 1325 EP - 1335 JF - ChemMedChem JO - ChemMedChem VL - 13 IS - 13 N2 - Computational methods, namely molecular dynamics (MD) simulations in combination with inhomogeneous fluid solvation theory (IFST) were used to retrospectively investigate various cases of ligand structure modifications that led to the displacement of binding site water molecules. Our findings are that water displacement per se is energetically unfavorable in the discussed examples, and that it is merely the fine balance between change in protein-ligand interaction energy, ligand solvation free energies, and binding site solvation free energies that determine if water displacement is favorable or not. We furthermore evaluated if we can reproduce experimental binding affinities by a computational approach combining changes in solvation free energies with changes in protein-ligand interaction energies and entropies. In two of the seven cases, this estimation led to large errors, implying that accurate predictions of relative binding free energies based on solvent thermodynamics is challenging. Nevertheless, MD simulations can provide insight regarding which water molecules can be targeted for displacement. SN - 1860-7187 UR - https://www.unboundmedicine.com/medline/citation/29726604/Thermodynamic_Insight_into_the_Effects_of_Water_Displacement_and_Rearrangement_upon_Ligand_Modifications_using_Molecular_Dynamics_Simulations_ L2 - https://doi.org/10.1002/cmdc.201800093 DB - PRIME DP - Unbound Medicine ER -