WScore: a flexible and accurate treatment of explicit water molecules in ligand-receptor docking.
Abstract
We have developed a new methodology for protein-ligand docking and scoring, WScore, incorporating a flexible description of explicit water molecules. The locations and thermodynamics of the waters are derived from a WaterMap molecular dynamics simulation. The water structure is employed to provide an atomic level description of ligand and protein desolvation. WScore also contains a detailed model for localized ligand and protein strain energy and integrates an MM-GBSA scoring component with these terms to assess delocalized strain of the complex. Ensemble docking is used to take into account induced fit effects on the receptor conformation, and protein reorganization free energies are assigned via fitting to experimental data. The performance of the method is evaluated for pose prediction, rank ordering of self-docked complexes, and enrichment in virtual screening, using a large data set of PDB complexes and compared with the Glide SP and Glide XP models; significant improvements are obtained.
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In WScore, the location and thermodynamics of explicit waters are predicted using WaterMap and integrated to the scoring function together with a desolvation term to penalize associated desolvation of polar or uncharged groups of protein or ligand.
“For instance, in the WScore docking methodology, the location and thermodynamics of explicit waters are predicted using WaterMap and integrated to the scoring function together with a desolvation term to penalize the associated desolvation of polar or uncharged groups of protein or ligand (Murphy et al., 2016).”
From Empirical scoring functions for structure-based virtual screening: applications, critical aspects, and challenges (2018) · cites this paper as Murphy et al., 2016
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- Authors
- Murphy, R. B., Repasky, M. P., Greenwood, J. R., Tubert-Brohman, I., Jerome, S., Annabhimoju, R., Boyles, N. A., Schmitz, C. D., Abel, R., Farid, R., & Friesner, R. A.
- Affiliations
- Schrodinger (United States) (US)
- Schrödinger, Inc., 120 West 45th Street, New York, New York 10036, United States
- Columbia University (US)
- Corresponding author
- Friesner, Richard A.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-04-22
- Volume
- 59
- Issue
- 9
- Pages
- 4364-4384
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2323252543
- Cited by
- 89
- References
- 57
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 4 · 2023: 11 · 2022: 11 · 2021: 12 · 2020: 5 · 2019: 9 · 2018: 11 · 2017: 9 · 2016: 4
- FWCI
- 10.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bill and Melinda Gates Foundation
- U.S. Department of Energy (DE-FG02-90ER14162)
- 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
- Physical Sciences › Physics and Astronomy › Atomic and Molecular Physics, and Optics › Advanced Chemical Physics Studies
- Keywords
- protein-ligand docking, explicit water molecules, desolvation, strain energy, MM-GBSA, ensemble docking, induced fit, docking scoring
- MeSH terms
- Hydrogen Bonding, Ligands, Receptors, Cell Surface, Water, Molecular Docking Simulation
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