ArticleProceedings of the National Academy of Sciences of the United States of America2017
Testing inhomogeneous solvation theory in structure-based ligand discovery.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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44 citing papers in PubMed.
- Article
- Chemical Distance-Based Acceleration of Large Library Docking with ChemSTEP.ACS central science · 2026Article
- Deep GIST: Deep Learning Models for Predicting the Distribution of Hydration Thermodynamics around Proteins.Journal of chemical information and modeling · 2026Article
- Unfreezing structural biology for drug discovery.Nature chemical biology · 2026Review
- Visualize Transient Water-Mediated Hydrogen Bonds Facilitating the Formation of Enzymatic Near-Attack Conformers.JACS Au · 2025Article
- Quantifying Spatially Resolved Hydration Thermodynamics Using Grid Inhomogeneous Solvation Theory [Article v1.0].Living journal of computational molecular science · 2025Article
- An experimental proxy of water displaceability for ligand discovery.Nature methods · 2025Article
- Development of Receptor Desolvation Scoring and Covalent Sampling in DOCK 6: Methods Evaluated on a RAS Test Set.Journal of chemical information and modeling · 2025Article
- The Art and Science of Molecular Docking.Annual review of biochemistry · 2024Review
- MPI-parallelization of the grid inhomogeneous solvation theory calculation.Journal of computational chemistry · 2024Article
- Free Energy Density of a Fluid and Its Role in Solvation and Binding.Journal of chemical theory and computation · 2024Article
- Considerations Around Structure-Based Drug Discovery for KRAS Using DOCK.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Assessing Genetic Algorithm-Based Docking Protocols for Prediction of Heparin Oligosaccharide Binding Geometries onto Proteins.Biomolecules · 2023Article
- The Advances and Limitations of the Determination and Applications of Water Structure in Molecular Engineering.International journal of molecular sciences · 2023Review
- WaterKit: Thermodynamic Profiling of Protein Hydration Sites.Journal of chemical theory and computation · 2023Article
- Pan-HSP90 ligand binding reveals isoform-specific differences in plasticity and water networks.Protein science : a publication of the Protein Society · 2023Article
- Heterogeneous and Allosteric Role of Surface Hydration for Protein-Ligand Binding.Journal of chemical theory and computation · 2023Article
- Large-Scale Ligand Perturbations of the Protein Conformational Landscape Reveal State-Specific Interaction Hotspots.Journal of medicinal chemistry · 2022Article
- Water Networks Repopulate Protein-Ligand Interfaces with Temperature.Angewandte Chemie (International ed. in English) · 2022Article
- Article
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9 authors.
Funding
Abstract
Binding-site water is often displaced upon ligand recognition, but is commonly neglected in structure-based ligand discovery. Inhomogeneous solvation theory (IST) has become popular for treating this effect, but it has not been tested in controlled experiments at atomic resolution. To do so, we turned to a grid-based version of this method, GIST, readily implemented in molecular docking. Whereas the term only improves docking modestly in retrospective ligand enrichment, it could be added without disrupting performance. We thus turned to prospective docking of large libraries to investigate GIST's impact on ligand discovery, geometry, and water structure in a model cavity site well-suited to exploring these terms. Although top-ranked docked molecules with and without the GIST term often overlapped, many ligands were meaningfully prioritized or deprioritized; some of these were selected for testing. Experimentally, 13/14 molecules prioritized by GIST did bind, whereas none of the molecules that it deprioritized were observed to bind. Nine crystal complexes were determined. In six, the ligand geometry corresponded to that predicted by GIST, for one of these the pose without the GIST term was wrong, and three crystallographic poses differed from both predictions. Notably, in one structure, an ordered water molecule with a high GIST displacement penalty was observed to stay in place. Inclusion of this water-displacement term can substantially improve the hit rates and ligand geometries from docking screens, although the magnitude of its effects can be small and its impact in drug binding sites merits further controlled studies.
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