ArticleJournal of medicinal chemistry2022
Large-Scale Ligand Perturbations of the Protein Conformational Landscape Reveal State-Specific Interaction Hotspots.
Article in Journal of medicinal chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 31 citations in OpenAlex.
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- Computational Evaluation of Statin Analogs Targeting HMG-CoA Reductase for Coronary Artery Disease Treatment.ChemistryOpen · 2026Article
- Discovery of novel natural compounds as PKCθ inhibitors: structure-based virtual screening and in vitro evaluation.Journal of computer-aided molecular design · 2026Article
- Synthesis, characterization, andFrontiers in chemistry · 2026Article
- An experimental proxy of water displaceability for ligand discovery.Nature methods · 2025Article
- Article
- Mapping Protein Conformational Landscapes from Crystallographic Drug Fragment Screens.Journal of chemical information and modeling · 2024Article
- Ensemble Docking as a Tool for the Rational Design of PeptidomimeticInternational journal of molecular sciences · 2024Article
- Mapping protein conformational landscapes from crystallographic drug fragment screens.bioRxiv : the preprint server for biology · 2024Article
- Activation Loop Plasticity and Active Site Coupling in the MAP Kinase, ERK2.Journal of molecular biology · 2023Article
- Binding Mechanism of Inhibitors to Heat Shock Protein 90 Investigated by Multiple Independent Molecular Dynamics Simulations and Prediction of Binding Free Energy.Molecules (Basel, Switzerland) · 2023Article
- FLEXR: automated multi-conformer model building using electron-density map sampling.Acta crystallographica. Section D, Structural biology · 2023Article
- Pan-HSP90 ligand binding reveals isoform-specific differences in plasticity and water networks.Protein science : a publication of the Protein Society · 2023Article
- Exploring the Therapeutic Potential of Virtual Screened Novel HER2 Inhibitors via QSAR, Molecular Docking and Dynamics Simulations.Dose-response : a publication of International Hormesis SocietyArticle
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Protein flexibility is important for ligand binding but often ignored in drug design. Considering proteins as ensembles rather than static snapshots creates opportunities to target dynamic proteins that lack FDA-approved drugs, such as the human chaperone, heat shock protein 90 (Hsp90). Hsp90α accommodates ligands with a dynamic lid domain, yet no comprehensive analysis relating lid conformations to ligand properties is available. To date, ∼300 ligand-bound Hsp90α crystal structures are deposited in the Protein Data Bank, which enables us to consider ligand binding as a perturbation of the protein conformational landscape. By estimating binding site volumes, we classified structures into distinct major and minor lid conformations. Supported by retrospective docking, each conformation creates unique hotspots that bind chemically distinguishable ligands. Clustering revealed insightful exceptions and the impact of crystal packing. Overall, Hsp90α's plasticity provides a cautionary tale of overinterpreting individual crystal structures and motivates an ensemble-based view of drug design.
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Registered trials
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