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J Med Chem. 2017 Nov 22;60(22):9239-9250. doi: 10.1021/acs.jmedchem.7b01113. Epub 2017 Nov 13.

Structure-Based Design and Discovery of New M2 Receptor Agonists.

Author information

1
Department of Pharmaceutical Chemistry, University of California, San Francisco , San Francisco, California 94158, United States.
2
Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Tel-Aviv University , Ramat Aviv, Israel.
3
Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University , Schuhstraße 19, 91052 Erlangen, Germany.
4
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville Victoria 3052, Australia.
5
Department of Pharmacology, University of California, San Diego , La Jolla, California 92093, United States.

Abstract

Muscarinic receptor agonists are characterized by apparently strict restraints on their tertiary or quaternary amine and their distance to an ester or related center. On the basis of the active state crystal structure of the muscarinic M2 receptor in complex with iperoxo, we explored potential agonists that lacked the highly conserved functionalities of previously known ligands. Using structure-guided pharmacophore design followed by docking, we found two agonists (compounds 3 and 17), out of 19 docked and synthesized compounds, that fit the receptor well and were predicted to form a hydrogen-bond conserved among known agonists. Structural optimization led to compound 28, which was 4-fold more potent than its parent 3. Fortified by the discovery of this new scaffold, we sought a broader range of chemotypes by docking 2.2 million fragments, which revealed another three micromolar agonists unrelated either to 28 or known muscarinics. Even pockets as tightly defined and as deeply studied as that of the muscarinic reveal opportunities for the structure-based design and the discovery of new chemotypes.

PMID:
29094937
PMCID:
PMC5836741
DOI:
10.1021/acs.jmedchem.7b01113
[Indexed for MEDLINE]
Free PMC Article

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