ArticleProceedings of the National Academy of Sciences of the United States of America2021
Energy penalties enhance flexible receptor docking in a model cavity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
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- Improving AlphaFold2 Performance in Virtual Screens Targeting GPCRs by Enhancing Binding-Site Conformational Sampling.Journal of chemical information and modeling · 2026Article
- Open-Source Molecular Docking and AI-Augmented Structure-Based Drug Design: Current Workflows, Challenges, and Opportunities.International journal of molecular sciences · 2026Review
- Unfreezing structural biology for drug discovery.Nature chemical biology · 2026Review
- From AI-AssistedPharmaceuticals (Basel, Switzerland) · 2025Review
- Conceptual density functional theory in drug discovery: an overview.Journal of molecular modeling · 2025Review
- Partitioning and Inhibition of Hemoglobin-Mediated Lipid Oxidation in Chicken by Components of Black Chokeberry Press Cake.Food science of animal resources · 2025Article
- Exploration of structure-activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment linking and active learning.Science advances · 2025Article
- Computational analysis of lupenone derivatives as potential inhibitor of human papillomavirus oncoprotein E6 associated cervical cancer.Scientific reports · 2025Article
- Modeling Boltzmann-weighted structural ensembles of proteins using artificial intelligence-based methods.Current opinion in structural biology · 2025Review
- Strategies for the drug development of cancer therapeutics.Frontiers in pharmacology · 2025Review
- Advances, opportunities, and challenges in methods for interrogating the structure activity relationships of natural products.Natural product reports · 2024Review
- The Art and Science of Molecular Docking.Annual review of biochemistry · 2024Review
- Expanding FTMap for Fragment-Based Identification of Pharmacophore Regions in Ligand Binding Sites.Journal of chemical information and modeling · 2024Article
- PopShift: A Thermodynamically Sound Approach to Estimate Binding Free Energies by Accounting for Ligand-Induced Population Shifts from a Ligand-Free Markov State Model.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
- Cucurbit[7]uril Enhances Distance Measurements of Spin-Labeled Proteins.Journal of the American Chemical Society · 2023Article
- General Theory of Specific Binding: Insights from a Genetic-Mechano-Chemical Protein Model.Molecular biology and evolution · 2022Article
- Fragment-based drug discovery-the importance of high-quality molecule libraries.Molecular oncology · 2022Review
- Large-Scale Ligand Perturbations of the Protein Conformational Landscape Reveal State-Specific Interaction Hotspots.Journal of medicinal chemistry · 2022Article
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6 authors.
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Abstract
Protein flexibility remains a major challenge in library docking because of difficulties in sampling conformational ensembles with accurate probabilities. Here, we use the model cavity site of T4 lysozyme L99A to test flexible receptor docking with energy penalties from molecular dynamics (MD) simulations. Crystallography with larger and smaller ligands indicates that this cavity can adopt three major conformations: open, intermediate, and closed. Since smaller ligands typically bind better to the cavity site, we anticipate an energy penalty for the cavity opening. To estimate its magnitude, we calculate conformational preferences from MD simulations. We find that including a penalty term is essential for retrospective ligand enrichment; otherwise, high-energy states dominate the docking. We then prospectively docked a library of over 900,000 compounds for new molecules binding to each conformational state. Absent a penalty term, the open conformation dominated the docking results; inclusion of this term led to a balanced sampling of ligands against each state. High ranked molecules were experimentally tested by T
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