Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite opposite effects in heart contraction.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
07 Jun 2024
07 Jun 2024
Historique:
received:
30
10
2023
accepted:
03
04
2024
medline:
8
6
2024
pubmed:
8
6
2024
entrez:
7
6
2024
Statut:
epublish
Résumé
Inherited cardiomyopathies are common cardiac diseases worldwide, leading in the late stage to heart failure and death. The most promising treatments against these diseases are small molecules directly modulating the force produced by β-cardiac myosin, the molecular motor driving heart contraction. Omecamtiv mecarbil and Mavacamten are two such molecules that completed phase 3 clinical trials, and the inhibitor Mavacamten is now approved by the FDA. In contrast to Mavacamten, Omecamtiv mecarbil acts as an activator of cardiac contractility. Here, we reveal by X-ray crystallography that both drugs target the same pocket and stabilize a pre-stroke structural state, with only few local differences. All-atom molecular dynamics simulations reveal how these molecules produce distinct effects in motor allostery thus impacting force production in opposite way. Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine.
Identifiants
pubmed: 38849353
doi: 10.1038/s41467-024-47587-9
pii: 10.1038/s41467-024-47587-9
doi:
Substances chimiques
omecamtiv mecarbil
2M19539ERK
Urea
8W8T17847W
MYK-461
0
Cardiac Myosins
EC 3.6.1.-
Ventricular Myosins
EC 3.6.1.-
Benzylamines
0
Uracil
56HH86ZVCT
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4885Subventions
Organisme : AFM-Téléthon (French Muscular Dystrophy Association)
ID : AFM 21805
Informations de copyright
© 2024. The Author(s).
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