ArticleMolecular pharmacology2013
Muscarinic receptors as model targets and antitargets for structure-based ligand discovery.
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 23 papers.
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Who cites it
23 citing papers in PubMed.
- Development of Mutant MBiochemistry · 2025Article
- GPCR drug discovery: new agents, targets and indications.Nature reviews. Drug discovery · 2025Review
- Visualizing agonist-induced M2 receptor activation regulated by aromatic ring dynamics.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- 2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery.Journal of medicinal chemistry · 2023Review
- Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor.Nature communications · 2023Article
- Antagonism of the Muscarinic Acetylcholine Type 1 Receptor Enhances Mitochondrial Membrane Potential and Expression of Respiratory Chain Components via AMPK in Human Neuroblastoma SH-SY5Y Cells and Primary Neurons.Molecular neurobiology · 2022Article
- One class classification for the detection of β2 adrenergic receptor agonists using single-ligand dynamic interaction data.Journal of cheminformatics · 2022Article
- Integration and Spatial Organization of Signaling by G Protein-Coupled Receptor Homo- and Heterodimers.Biomolecules · 2021Review
- G protein-coupled receptors: structure- and function-based drug discovery.Signal transduction and targeted therapy · 2021Review
- Performance of virtual screening against GPCR homology models: Impact of template selection and treatment of binding site plasticity.PLoS computational biology · 2020Article
- G Protein-Coupled Receptors in Asthma Therapy: Pharmacology and Drug Action.Pharmacological reviews · 2020Review
- Exploring G Protein-Coupled Receptors (GPCRs) Ligand Space via Cheminformatics Approaches: Impact on Rational Drug Design.Frontiers in pharmacology · 2018Review
- Discovery of new GPCR ligands to illuminate new biology.Nature chemical biology · 2017Article
- M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss.The Journal of clinical investigation · 2017Article
- G-protein coupled receptors: advances in simulation and drug discovery.Current opinion in structural biology · 2016Review
- Identifying ligands at orphan GPCRs: current status using structure-based approaches.British journal of pharmacology · 2016Review
- Accelerated structure-based design of chemically diverse allosteric modulators of a muscarinic G protein-coupled receptor.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Small-Molecule Allosteric Modulators of the Protein Kinase PDK1 from Structure-Based Docking.Journal of medicinal chemistry · 2015Article
- What can crystal structures of aminergic receptors tell us about designing subtype-selective ligands?Pharmacological reviews · 2015Review
- Muscarinic acetylcholine receptors: novel opportunities for drug development.Nature reviews. Drug discovery · 2014Review
Corrections and comments
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Authors and funding
10 authors.
Funding
Abstract
G protein-coupled receptors (GPCRs) regulate virtually all aspects of human physiology and represent an important class of therapeutic drug targets. Many GPCR-targeted drugs resemble endogenous agonists, often resulting in poor selectivity among receptor subtypes and restricted pharmacologic profiles. The muscarinic acetylcholine receptor family exemplifies these problems; thousands of ligands are known, but few are receptor subtype-selective and nearly all are cationic in nature. Using structure-based docking against the M2 and M3 muscarinic receptors, we screened 3.1 million molecules for ligands with new physical properties, chemotypes, and receptor subtype selectivities. Of 19 docking-prioritized molecules tested against the M2 subtype, 11 had substantial activity and 8 represented new chemotypes. Intriguingly, two were uncharged ligands with low micromolar to high nanomolar Ki values, an observation with few precedents among aminergic GPCRs. To exploit a single amino-acid substitution among the binding pockets between the M2 and M3 receptors, we selected molecules predicted by docking to bind to the M3 and but not the M2 receptor. Of 16 molecules tested, 8 bound to the M3 receptor. Whereas selectivity remained modest for most of these, one was a partial agonist at the M3 receptor without measurable M2 agonism. Consistent with this activity, this compound stimulated insulin release from a mouse β-cell line. These results support the ability of structure-based discovery to identify new ligands with unexplored chemotypes and physical properties, leading to new biologic functions, even in an area as heavily explored as muscarinic pharmacology.
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