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Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists

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 M...

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Autores principales: Liu, Hongtao, Hofmann, Josefa, Fish, Inbar, Schaake, Benjamin, Eitel, Katrin, Bartuschat, Amelie, Kaindl, Jonas, Rampp, Hannelore, Banerjee, Ashutosh, Hübner, Harald, Clark, Mary J., Vincent, Sandra G., Fisher, John T., Heinrich, Markus R., Hirata, Kunio, Liu, Xiangyu, Sunahara, Roger K., Shoichet, Brian K., Kobilka, Brian K., Gmeiner, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255194/
https://www.ncbi.nlm.nih.gov/pubmed/30404914
http://dx.doi.org/10.1073/pnas.1813988115
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author Liu, Hongtao
Hofmann, Josefa
Fish, Inbar
Schaake, Benjamin
Eitel, Katrin
Bartuschat, Amelie
Kaindl, Jonas
Rampp, Hannelore
Banerjee, Ashutosh
Hübner, Harald
Clark, Mary J.
Vincent, Sandra G.
Fisher, John T.
Heinrich, Markus R.
Hirata, Kunio
Liu, Xiangyu
Sunahara, Roger K.
Shoichet, Brian K.
Kobilka, Brian K.
Gmeiner, Peter
author_facet Liu, Hongtao
Hofmann, Josefa
Fish, Inbar
Schaake, Benjamin
Eitel, Katrin
Bartuschat, Amelie
Kaindl, Jonas
Rampp, Hannelore
Banerjee, Ashutosh
Hübner, Harald
Clark, Mary J.
Vincent, Sandra G.
Fisher, John T.
Heinrich, Markus R.
Hirata, Kunio
Liu, Xiangyu
Sunahara, Roger K.
Shoichet, Brian K.
Kobilka, Brian K.
Gmeiner, Peter
author_sort Liu, Hongtao
collection PubMed
description 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.
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spelling pubmed-62551942018-11-30 Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists Liu, Hongtao Hofmann, Josefa Fish, Inbar Schaake, Benjamin Eitel, Katrin Bartuschat, Amelie Kaindl, Jonas Rampp, Hannelore Banerjee, Ashutosh Hübner, Harald Clark, Mary J. Vincent, Sandra G. Fisher, John T. Heinrich, Markus R. Hirata, Kunio Liu, Xiangyu Sunahara, Roger K. Shoichet, Brian K. Kobilka, Brian K. Gmeiner, Peter Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2018-11-20 2018-11-07 /pmc/articles/PMC6255194/ /pubmed/30404914 http://dx.doi.org/10.1073/pnas.1813988115 Text en Copyright © 2018 the Author(s). Published by PNAS. http://creativecommons.org/licenses/by/4.0/ This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Liu, Hongtao
Hofmann, Josefa
Fish, Inbar
Schaake, Benjamin
Eitel, Katrin
Bartuschat, Amelie
Kaindl, Jonas
Rampp, Hannelore
Banerjee, Ashutosh
Hübner, Harald
Clark, Mary J.
Vincent, Sandra G.
Fisher, John T.
Heinrich, Markus R.
Hirata, Kunio
Liu, Xiangyu
Sunahara, Roger K.
Shoichet, Brian K.
Kobilka, Brian K.
Gmeiner, Peter
Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists
title Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists
title_full Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists
title_fullStr Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists
title_full_unstemmed Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists
title_short Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists
title_sort structure-guided development of selective m3 muscarinic acetylcholine receptor antagonists
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255194/
https://www.ncbi.nlm.nih.gov/pubmed/30404914
http://dx.doi.org/10.1073/pnas.1813988115
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