Cited by 393Computational Drug Discovery MethodsProtein Structure and DynamicsProtein Interaction Studies and Fluorescence Analysis

Modeling water molecules in protein-ligand docking using GOLD.

Verdonk, Marcel L., Chessari, Gianni, Cole, Jason C., Hartshorn, Michael J., Murray, Christopher W., Nissink, J. Willem M., Taylor, Richard D., Taylor, Robin·2005·Journal of Medicinal Chemistry

Abstract

We implemented a novel approach to score water mediation and displacement in the protein-ligand docking program GOLD. The method allows water molecules to switch on and off and to rotate around their three principal axes. A constant penalty, sigma(p), representing the loss of rigid-body entropy, is added for water molecules that are switched on, hence rewarding water displacement. We tested the methodology in an extensive validation study. First, sigma(p) is optimized against a training set of 58 protein-ligand complexes. For this training set, our algorithm correctly predicts water mediation/displacement in approximately 92% of the cases. We observed small improvements in the quality of the predicted binding modes for water-mediated complexes. In the second part of this work, an entirely independent set of 225 complexes is used. For this test set, our algorithm correctly predicts water mediation/displacement in approximately 93% of the cases. Improvements in binding mode quality were observed for individual water-mediated complexes.

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Crossref · 10.1021/jm050543p

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  • The GOLD program considers an all-atom and flexible water model able to rotate around its three principal axes, and rewards water displacement in the GoldScore or ChemScore scoring functions according to a balance between loss of rigid-body entropy and change in interaction energies on binding to the protein cavity.

    “The GOLD program considers all-atom and flexible water model able to rotate around its three principal axes, and rewards water displacement in the GoldScore or ChemScore scoring functions according to a balance between the loss of rigid-body entropy and the change in the interaction energies on binding to the protein cavity (Verdonk et al., 2005).”

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Authors
Verdonk, M. L., Chessari, G., Cole, J. C., Hartshorn, M. J., Murray, C. W., Nissink, J. W. M., Taylor, R. D., & Taylor, R.
Affiliations
Cambridge Crystallographic Data Centre (GB)
Corresponding author
Verdonk, Marcel L.
Venue
Journal of Medicinal Chemistry
Published
2005-09-14
Volume
48
Issue
20
Pages
6504-6515
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
OpenAlex
W2063535987
Cited by
393
References
45
Citations by year
2026: 8 · 2025: 13 · 2024: 18 · 2023: 6 · 2022: 14 · 2021: 24 · 2020: 20 · 2019: 18 · 2018: 14 · 2017: 24 · 2016: 23 · 2015: 26 · 2014: 19 · 2013: 19 · 2012: 29
FWCI
16.09
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Medicinal Chemistry (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
Keywords
water displacement, protein-ligand docking, binding mode prediction
MeSH terms
Algorithms, Bacterial Proteins, Binding Sites, Carrier Proteins, Ligands, Lipoproteins, Models, Molecular, Molecular Conformation, Protein Binding, Proteins, Thymidine Kinase, Water, Factor Xa, HIV Protease

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