Modeling water molecules in protein-ligand docking using GOLD.
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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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).”
From Empirical scoring functions for structure-based virtual screening: applications, critical aspects, and challenges (2018) · cites this paper as 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.
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- 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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