ArticleJournal of chemical theory and computation2021
Force Field Optimization Guided by Small Molecule Crystal Lattice Data Enables Consistent Sub-Angstrom Protein-Ligand Docking.
Article in Journal of chemical theory and computation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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57 citing papers in PubMed.
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- Structure-guided compound prioritization strategy for virtual screening identifies putative binders for the nuclear receptor LRH-1.bioRxiv : the preprint server for biology · 2026Article
- A hERG Blocker Facilitates KbioRxiv : the preprint server for biology · 2026Article
- Reproducibility, validation, and failure modes across classical and AI-driven molecular docking.Journal of computer-aided molecular design · 2026Review
- Assessing the Generalizability of Machine Learning and Physics-Based Methods with DNA-Encoded Libraries.bioRxiv : the preprint server for biology · 2026Article
- Structural basis of the sweat odorant HMHA recognition by the human odorant receptor OR52E8.Communications biology · 2026Article
- Heat- and PIP2-dependent TRPM4 activity underlies mutually exclusive human diseases.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Interactions of Cyclic Peptides Ribifolin and Gramicidin S with Montmorillonite Surface by Molecular Modeling.ACS omega · 2026Article
- Small-molecule binding and sensing with a designed protein family.Nature communications · 2026Article
- Structural basis of odorant recognition by a mammalian class II odorant receptor.Science advances · 2026Article
- Inhibition of CaV1.4 channels by CaV3 channel antagonists ML218 and Z944.The Journal of general physiology · 2026Article
- Modeling protein-small molecule conformational ensembles with PLACER.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Undirected Exploration of Binding Pockets with Flexible Topology.Journal of chemical theory and computation · 2025Article
- Modeling protein-small molecule conformational ensembles with PLACER.bioRxiv : the preprint server for biology · 2025Article
- Advanced Strategies in Phage Research: Innovations, Applications, and Challenges.Microorganisms · 2025Review
- Deep learning molecular interaction motifs from receptor structures alone.Journal of cheminformatics · 2025Article
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- Engineering of Transmembrane Alkane Monooxygenases to Improve a Key Reaction Step in the Synthesis of Polymer Precursor Tulipalin A.Angewandte Chemie (International ed. in English) · 2025Article
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5 authors.
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Abstract
Accurate and rapid calculation of protein-small molecule interaction free energies is critical for computational drug discovery. Because of the large chemical space spanned by drug-like molecules, classical force fields contain thousands of parameters describing atom-pair distance and torsional preferences; each parameter is typically optimized independently on simple representative molecules. Here, we describe a new approach in which small molecule force field parameters are jointly optimized guided by the rich source of information contained within thousands of available small molecule crystal structures. We optimize parameters by requiring that the experimentally determined molecular lattice arrangements have lower energy than all alternative lattice arrangements. Thousands of independent crystal lattice-prediction simulations were run on each of 1386 small molecule crystal structures, and energy function parameters of an implicit solvent energy model were optimized, so native crystal lattice arrangements had the lowest energy. The resulting energy model was implemented in Rosetta, together with a rapid genetic algorithm docking method employing grid-based scoring and receptor flexibility. The success rate of bound structure recapitulation in cross-docking on 1112 complexes was improved by more than 10% over previously published methods, with solutions within <1 Å in over half of the cases. Our results demonstrate that small molecule crystal structures are a rich source of information for guiding molecular force field development, and the improved Rosetta energy function should increase accuracy in a wide range of small molecule structure prediction and design studies.
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