ArticleJournal of medicinal chemistry2018
qFit-ligand Reveals Widespread Conformational Heterogeneity of Drug-Like Molecules in X-Ray Electron Density Maps.
Article in Journal of medicinal chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
What it found
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Who cites it
41 citing papers in PubMed, 41 citations in OpenAlex.
- Structural Plasticity and Ligand Promiscuity of CYP3A4 Revealed by Cryo-EM.bioRxiv : the preprint server for biology · 2026Article
- Benchmarking Docking Protocols on Predicting Alternative Binding Modes.Journal of chemical information and modeling · 2026Article
- Resolving the ambiguous binding site of quercetin at the calcineurin subunit junction using funnel metadynamics with deep learning collective variables.Journal of computer-aided molecular design · 2026Article
- Unfreezing structural biology for drug discovery.Nature chemical biology · 2026Review
- Computational Ligand-Binding Site Prediction.Advances in experimental medicine and biology · 2026Review
- Structural comparison of substrate-binding pockets of serine β-lactamases in classes A, C, and D.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- Hybrid Antibiotics Targeting the Bacterial Ribosome.ACS central science · 2025Article
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- Exploration of structure-activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment linking and active learning.Science advances · 2025Article
- Mapping allosteric rewiring in related protein structures from collections of crystallographic multiconformer models.bioRxiv : the preprint server for biology · 2025Article
- Advances in uncovering the mechanisms of macromolecular conformational entropy.Nature chemical biology · 2025Review
- Expanding Automated Multiconformer Ligand Modeling to Macrocycles and Fragments.bioRxiv : the preprint server for biology · 2025Article
- Crystallographic and biochemical analyses of a far-red allophycocyanin to address the mechanism of the super-red-shift.Photosynthesis research · 2024Article
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- Uncovering Protein Ensembles: Automated Multiconformer Model Building for X-ray Crystallography and Cryo-EM.bioRxiv : the preprint server for biology · 2024Article
- High-Confidence Placement of Fragments into Electron Density Using Anomalous Diffraction-A Case Study Using Hits Targeting SARS-CoV-2 Non-Structural Protein 1.International journal of molecular sciences · 2023Article
- FLEXR: automated multi-conformer model building using electron-density map sampling.Acta crystallographica. Section D, Structural biology · 2023Article
- Room-temperature crystallography reveals altered binding of small-molecule fragments to PTP1B.eLife · 2023Article
- A Distributional Model of Bound Ligand Conformational Strain: From Small Molecules up to Large Peptidic Macrocycles.Journal of medicinal chemistry · 2023Article
- Determining biomolecular structures near room temperature using X-ray crystallography: concepts, methods and future optimization.Acta crystallographica. Section D, Structural biology · 2023Article
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
Proteins and ligands sample a conformational ensemble that governs molecular recognition, activity, and dissociation. In structure-based drug design, access to this conformational ensemble is critical to understand the balance between entropy and enthalpy in lead optimization. However, ligand conformational heterogeneity is currently severely underreported in crystal structures in the Protein Data Bank, owing in part to a lack of automated and unbiased procedures to model an ensemble of protein-ligand states into X-ray data. Here, we designed a computational method, qFit-ligand, to automatically resolve conformationally averaged ligand heterogeneity in crystal structures, and applied it to a large set of protein receptor-ligand complexes. In an analysis of the cancer related BRD4 domain, we found that up to 29% of protein crystal structures bound with drug-like molecules present evidence of unmodeled, averaged, relatively isoenergetic conformations in ligand-receptor interactions. In many retrospective cases, these alternate conformations were adventitiously exploited to guide compound design, resulting in improved potency or selectivity. Combining qFit-ligand with high-throughput screening or multitemperature crystallography could therefore augment the structure-based drug design toolbox.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.