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
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
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.
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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