Cardiomyopathies are heart muscle diseases caused by several factors with a common cause being point mutations within the genes encoding the various proteins of the cardiac sarcomere. Genetic cardiomyopathies can be of various forms with the most prevalent form being hypertrophic cardiomyopathy or HCM. This is defined by the thickening of the left ventricular wall leading to obstruction in the blood flow to and from the heart. Due to the complexity of the disease, designing therapeutics has been challenging.
Mavacamten is a first-in-class novel medication, recently FDA approved, for the treatment of HCM and it is sold under the brand name Camzyos. This drug is termed as a cardiac myosin inhibitor and has been identified based on a high-throughput screening method. This drug binds directly to the human cardiac β myosin and is highly selective. Though the drug has been observed to affect multiple steps of the myosin cross-bridge cycle, not much is understood about its mechanism of action. This study aims to highlight the effect of the drug on the ATP hydrolysis step needed to generate force in heart muscle. We study the drug in presence as well as absence of HCM mutations using Transition Path Sampling. The results allow us to study the changes in chemistry induced by the drug both in the presence and absence of mutations and provide the effect of the drug on the rate of the chemical step. These insights are essential to understand the differential effect of both the mutations and of the drug as well as aid in developing new targeted treatments for genetic cardiac diseases.
Graduate Student, Chemistry and Biochemistry, The University of Arizona