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Proc Natl Acad Sci U S A. 2018 Nov 20;115(47):12046-12050. doi: 10.1073/pnas.1813988115. Epub 2018 Nov 7.

Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists.

Author information

1
Beijing Advanced Innovation Center for Structural Biology, School of Medicine, Tsinghua University, 100084 Beijing, China.
2
Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058 Erlangen, Germany.
3
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158.
4
Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, 6997801 Ramat Aviv, Israel.
5
Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093.
6
Department of Biomedical & Molecular Sciences, Queen's University, Kingston, ON, Canada K7L 3N6.
7
Division of Respirology, Department of Medicine, Queen's University, Kingston, ON, Canada K7L 3N6.
8
Advanced Photon Technology Division, Research Infrastructure Group, SR Life Science Instrumentation Unit, RIKEN/SPring-8 Center, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5148, Japan.
9
Beijing Advanced Innovation Center for Structural Biology, School of Medicine, Tsinghua University, 100084 Beijing, China; liu_xy@mail.tsinghua.edu.cn bshoichet@gmail.com kobilka@stanford.edu peter.gmeiner@fau.de.
10
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158; liu_xy@mail.tsinghua.edu.cn bshoichet@gmail.com kobilka@stanford.edu peter.gmeiner@fau.de.
11
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.
12
Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058 Erlangen, Germany; liu_xy@mail.tsinghua.edu.cn bshoichet@gmail.com kobilka@stanford.edu peter.gmeiner@fau.de.

Abstract

Drugs that treat chronic obstructive pulmonary disease by antagonizing the M3 muscarinic acetylcholine receptor (M3R) have had a significant effect on health, but can suffer from their lack of selectivity against the M2R subtype, which modulates heart rate. Beginning with the crystal structures of M2R and M3R, we exploited a single amino acid difference in their orthosteric binding pockets using molecular docking and structure-based design. The resulting M3R antagonists had up to 100-fold selectivity over M2R in affinity and over 1,000-fold selectivity in vivo. The crystal structure of the M3R-selective antagonist in complex with M3R corresponded closely to the docking-predicted geometry, providing a template for further optimization.

KEYWORDS:

G protein-coupled receptor; crystal structure; drug design; muscarinic receptor; subtype selectivity

PMID:
30404914
PMCID:
PMC6255194
DOI:
10.1073/pnas.1813988115
[Indexed for MEDLINE]
Free PMC Article

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