ArticleMolecular pharmacology2013
Structure-based ligand discovery targeting orthosteric and allosteric pockets of dopamine receptors.
Article in Molecular pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
43 citing papers in PubMed, 91 citations in OpenAlex.
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- Structure-based discovery of positive allosteric modulators of the AProceedings of the National Academy of Sciences of the United States of America · 2025Article
- AI meets physics in computational structure-based drug discovery for GPCRs.npj drug discovery · 2025Review
- AlphaFold accelerated discovery of psychotropic agonists targeting the trace amine-associated receptor 1.Science advances · 2024Article
- Review on allosteric modulators of dopamine receptors so far.Health science reports · 2024Article
- Computational drug development for membrane protein targets.Nature biotechnology · 2024Review
- Orphan G protein-coupled receptors: the ongoing search for a home.Frontiers in pharmacology · 2024Review
- Allosteric Modulators of Dopamine DMolecules (Basel, Switzerland) · 2022Review
- Allosteric modulation of dopamine DPharmacological reports : PR · 2022Article
- In Silico Prediction and Validation of CB2 Allosteric Binding Sites to Aid the Design of Allosteric Modulators.Molecules (Basel, Switzerland) · 2022Article
- Probe Confined Dynamic Mapping for G Protein-Coupled Receptor Allosteric Site Prediction.ACS central science · 2021Article
- Crystal structure of dopamine D1 receptor in complex with G protein and a non-catechol agonist.Nature communications · 2021Article
- Structure-Based Virtual Screening of Ultra-Large Library Yields Potent Antagonists for a Lipid GPCR.Biomolecules · 2020Article
- Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective DJournal of medicinal chemistry · 2020Article
- Targeting the C-Terminal Domain Small Phosphatase 1.Life (Basel, Switzerland) · 2020Review
- Article
- Performance of virtual screening against GPCR homology models: Impact of template selection and treatment of binding site plasticity.PLoS computational biology · 2020Article
- Article
- Discovery of CNS-Like D3R-Selective Antagonists Using 3D Pharmacophore Guided Virtual Screening.Molecules (Basel, Switzerland) · 2018Article
- Binding kinetics of cariprazine and aripiprazole at the dopamine DScientific reports · 2018Article
Corrections and comments
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Authors and funding
8 authors at 5 institutions in 2 countries.
Funding
Abstract
Small molecules targeting allosteric pockets of G protein-coupled receptors (GPCRs) have a great therapeutic potential for the treatment of neurologic and other chronic disorders. Here we performed virtual screening for orthosteric and putative allosteric ligands of the human dopamine D3 receptor (D3R) using two optimized crystal-structure-based models: the receptor with an empty binding pocket (D3R(APO)), and the receptor complex with dopamine (D3R(Dopa)). Subsequent biochemical and functional characterization revealed 14 novel ligands with a binding affinity of better than 10 μM in the D3R(APO) candidate list (56% hit rate), and 8 novel ligands in the D3R(Dopa) list (32% hit rate). Most ligands in the D3R(APO) model span both orthosteric and extended pockets and behave as antagonists at D3R, with compound 7 showing the highest potency of dopamine inhibition (IC₅₀ = 7 nM). In contrast, compounds identified by the D3R(Dopa) model are predicted to occupy an allosteric site at the extracellular extension of the pocket, and they all lack the anchoring amino group. Compounds targeting the allosteric site display a variety of functional activity profiles, where behavior of at least two compounds (23 and 26) is consistent with noncompetitive allosteric modulation of dopamine signaling in the extracellular signal-regulated kinase 1 and 2 phosphorylation and β-arrestin recruitment assays. The high affinity and ligand efficiency of the chemically diverse hits identified in this study suggest utility of structure-based screening targeting allosteric sites of GPCRs.
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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.