Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists
| Autor: | Hannelore Rampp, Markus R. Heinrich, Xiangyu Liu, Katrin Eitel, Inbar Fish, Peter Gmeiner, Sandra G. Vincent, Roger K. Sunahara, Ashutosh Banerjee, Hongtao Liu, Harald Hübner, Josefa Hofmann, Mary J. Clark, Brian K. Kobilka, Kunio Hirata, Amelie L. Bartuschat, John T. Fisher, Brian K. Shoichet, Jonas Kaindl, Benjamin Schaake |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
crystal structure drug design 1.1 Normal biological development and functioning Pulmonary disease Muscarinic Antagonists Crystallography X-Ray muscarinic receptor 03 medical and health sciences 0302 clinical medicine Underpinning research In vivo MD Multidisciplinary Muscarinic acetylcholine receptor Humans Amino Acid Sequence G protein-coupled receptor Single amino acid Pharmacology Receptor Muscarinic M3 Receptor Muscarinic M2 Crystallography Multidisciplinary Chemistry Antagonist subtype selectivity Biological Sciences Acetylcholine 3. Good health Molecular Docking Simulation Muscarinic M3 030104 developmental biology Muscarinic M2 Membrane protein 5.1 Pharmaceuticals 030220 oncology & carcinogenesis X-Ray Biophysics Generic health relevance Development of treatments and therapeutic interventions Selectivity Receptor |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 115, iss 47 Liu, Hongtao; Hofmann, Josefa; Fish, Inbar; Schaake, Benjamin; Eitel, Katrin; Bartuschat, Amelie; et al.(2018). Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 115(47), 12046-12050. doi: 10.1073/pnas.1813988115. UC San Diego: Retrieved from: http://www.escholarship.org/uc/item/7dq0974t Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance The development of selective antagonists for muscarinic acetylcholine receptors is challenging due to high homology in orthosteric binding sites among subtypes. Starting from a single amino acid difference in the orthosteric pockets in M2 muscarinic acetylcholine receptor (M2R) and M3R, we developed an M3R-selective antagonist using molecular docking and structure-based design. The resulting M3R antagonist showed up to 100-fold selectivity over the M2R in affinity and 1,000-fold selectivity in vivo. The docking-predicted geometry was further confirmed by a 3.1 Å crystal structure of M3R in complex with the selective antagonist. The potential of structure-based design to develop selective drugs with reduced off-target effects is supported by this study. 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. |
| Databáze: | OpenAIRE |
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