ArticleJournal of the American Chemical Society2009
Energetics of displacing water molecules from protein binding sites: consequences for ligand optimization.
Article in Journal of the American Chemical Society, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 97 papers.
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Who cites it
97 citing papers in PubMed.
- Free energy calculations in molecular modeling: from classical methods to machine learning.Journal of molecular modeling · 2026Review
- Water Networks as Hydrophobic Recognition Motifs in Proteins.Angewandte Chemie (International ed. in English) · 2026Article
- Theranostic Potential of Copper-64 ATSM Targeting MTHFD2: An In Silico Perspective on Hypoxia-Selective Imaging and Therapy.Cell biochemistry and biophysics · 2025Article
- Advancing Binding Affinity Calculations: A Non-Equilibrium Simulations Approach for Calculation of Relative Binding Free Energies in Systems with Trapped Waters.Journal of chemical theory and computation · 2025Article
- An experimental proxy of water displaceability for ligand discovery.Nature methods · 2025Article
- Understanding the HIV-CA protein and the ligands that bind at the N-terminal domain (NTD) - C-terminal domain (CTD) interface.RSC medicinal chemistry · 2025Review
- Rapid Access to Small Molecule Conformational Ensembles in Organic Solvents Enabled by Graph Neural Network-Based Implicit Solvent Model.Journal of the American Chemical Society · 2025Article
- A New Dawn for Targeted Cancer Therapy: Small Molecule Covalent Binding Inhibitor Targeting K-Ras (G12C).Current medicinal chemistry · 2025Review
- Leveraging a Separation of States Method for Relative Binding Free Energy Calculations in Systems with Trapped Waters.Journal of chemical theory and computation · 2024Article
- Modeling Ligand Binding Site Water Networks with Site Identification by Ligand Competitive Saturation: Impact on Ligand Binding Orientations and Relative Binding Affinities.Journal of chemical theory and computation · 2024Article
- Incorporating Water Molecules into Highly Accurate Binding Affinity Prediction for Proteins and Ligands.International journal of molecular sciences · 2024Article
- Indazole to 2-Cyanoindole Scaffold Progression for Mycobacterial Lipoamide Dehydrogenase Inhibitors Achieves Extended Target Residence Time and Improved Antibacterial Activity.Angewandte Chemie (International ed. in English) · 2024Article
- Enthalpic Classification of Water Molecules in Target-Ligand Binding.Journal of chemical information and modeling · 2024Article
- Investigation of molecular details of a bacterial cationic amino acid transporter (GkApcT) during arginine transportation using molecular dynamics simulation and umbrella sampling techniques.Journal of molecular modeling · 2023Article
- WaterKit: Thermodynamic Profiling of Protein Hydration Sites.Journal of chemical theory and computation · 2023Article
- Heterogeneous and Allosteric Role of Surface Hydration for Protein-Ligand Binding.Journal of chemical theory and computation · 2023Article
- Accounting for Solvation Correlation Effects on the Thermodynamics of Water Networks in Protein Cavities.Journal of chemical information and modeling · 2023Article
- In Silico Evaluation of the Thr58-Associated Conserved Water with KRAS Switch-II Pocket Binders.Journal of chemical information and modeling · 2023Article
- Conserved Water Networks Identification for Drug Design Using Density Clustering Approaches on Positional and Orientational Data.Journal of chemical information and modeling · 2022Article
- General Theory of Specific Binding: Insights from a Genetic-Mechano-Chemical Protein Model.Molecular biology and evolution · 2022Article
37 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors.
Funding
Abstract
A strategy in drug design is to consider enhancing the affinity of lead molecules with structural modifications that displace water molecules from a protein binding site. Because success of the approach is uncertain, clarification of the associated energetics was sought in cases where similar structural modifications yield qualitatively different outcomes. Specifically, free-energy perturbation calculations were carried out in the context of Monte Carlo statistical mechanics simulations to investigate ligand series that feature displacement of ordered water molecules in the binding sites of scytalone dehydratase, p38-alphaMAP kinase, and EGFR kinase. The change in affinity for a ligand modification is found to correlate with the ease of displacement of the ordered water molecule. However, as in the EGFR example, the binding affinity may diminish if the free-energy increase due to the removal of the bound water molecule is not more than compensated by the additional interactions of the water-displacing moiety. For accurate computation of the effects of ligand modifications, a complete thermodynamic analysis is shown to be needed. It requires identification of the location of water molecules in the protein-ligand interface and evaluation of the free-energy changes associated with their removal and with the introduction of the ligand modification. Direct modification of the ligand in free-energy calculations is likely to trap the ordered molecule and provide misleading guidance for lead optimization.
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