Muscarinic receptors as model targets and antitargets for structure-based ligand discovery

Kruse AC, Weiss DR, Rossi M, Hu J, Hu K, Eitel K, Gmeiner P, Wess J, Kobilka BK, Shoichet BK (2013)

Publication Language: English

Publication Type: Journal article, Original article

Publication year: 2013

Journal

Molecular Pharmacology American Society for Pharmacology and Experimental Therapeutics (ASPET)

Original Authors: Kruse A.C., Weiss D.R., Rossi M., Hu J., Hu K., Eitel K., Gmeiner P., Wess J., Kobilka B.K., Shoichet B.K.

Publisher: American Society for Pharmacology and Experimental Therapeutics (ASPET)

Book Volume: 84

Pages Range: 528-540

Journal Issue: 4

DOI: 10.1124/mol.113.087551

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 M and M 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 M subtype, 11 had substantial activity and 8 represented new chemotypes. Intriguingly, two were uncharged ligands with low micromolar to high nanomolar K values, an observation with few precedents among aminergic GPCRs. To exploit a single amino-acid substitution among the binding pockets between the M and M receptors, we selected molecules predicted by docking to bind to the M and but not the M receptor. Of 16 molecules tested, 8 bound to the M receptor. Whereas selectivity remained modest formost of these, one was a partial agonist at the M receptor without measurable M 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.

Authors with CRIS profile

Katrin Eitel Lehrstuhl für Pharmazeutische Chemie Peter Gmeiner Lehrstuhl für Pharmazeutische Chemie

Additional Organisation(s)

Emil-Fischer-Zentrum (Emil Fischer Center)

Involved external institutions

Stanford University US United States (USA) (US) University of California San Francisco (UCSF) US United States (USA) (US) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK / NIDDKD) US United States (USA) (US)

How to cite

APA:

Kruse, A.C., Weiss, D.R., Rossi, M., Hu, J., Hu, K., Eitel, K.,... Shoichet, B.K. (2013). Muscarinic receptors as model targets and antitargets for structure-based ligand discovery. Molecular Pharmacology, 84(4), 528-540. https://dx.doi.org/10.1124/mol.113.087551

MLA:

Kruse, Andrew C., et al. "Muscarinic receptors as model targets and antitargets for structure-based ligand discovery." Molecular Pharmacology 84.4 (2013): 528-540.

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