1. Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite opposite effects in heart contraction.
- Author
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Auguin, Daniel, Robert-Paganin, Julien, Réty, Stéphane, Kikuti, Carlos, David, Amandine, Theumer, Gabriele, Schmidt, Arndt W., Knölker, Hans-Joachim, and Houdusse, Anne
- Subjects
CARDIAC contraction ,HEART ,MYOSIN ,MOLECULAR motor proteins ,CLINICAL trials ,SMALL molecules ,MOLECULAR dynamics - Abstract
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. Omecamtiv mecarbil and Mavacamten are small molecules directly modulating the force produced by β-cardiac myosin. In this work, the authors describe how the modulators Omecamtiv mecarbil and Mavacamten can have opposite effects on cardiac myosin force production despite occupying the same pocket. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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