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

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.

SUBMITTER: Liu H

PROVIDER: S-EPMC6255194 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Liu Hongtao H Hofmann Josefa J Fish Inbar I Schaake Benjamin B Eitel Katrin K Bartuschat Amelie A Kaindl Jonas J Rampp Hannelore H Banerjee Ashutosh A Hübner Harald H Clark Mary J MJ Vincent Sandra G SG Fisher John T JT Heinrich Markus R MR Hirata Kunio K Liu Xiangyu X Sunahara Roger K RK Shoichet Brian K BK Kobilka Brian K BK Gmeiner Peter P

Proceedings of the National Academy of Sciences of the United States of America 20181107 47

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 select ...[more]

PMID: 30404914

Dataset Information

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

Publications

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

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