Insights into the Mechanism of the Cardiac Drug Omecamtiv Mecarbil─A Computational Study

Omecamtiv mecarbil (OM) is a positive inotrope that is thought to bind directly to an allosteric site of the β-cardiac myosin. The drug is under investigation for the treatment of systolic heart failure. The drug is classified as a cardiac myosin modulator and has been observed to affect multiple vital steps of the cross-bridge cycle including the recovery stroke and the chemical step. We explored the free-energy surface of the recovery stroke of the human cardiac β-myosin in the presence of OM to determine its influence on this process. We also investigated the effects of OM on the recovery stroke in the presence of genetic cardiomyopathic mutations R712L, F764L, and P710R using metadynamics. We also utilized the method of transition path sampling to generate an unbiased ensemble of reactive trajectories for the ATP hydrolysis step in the presence of OM that were able to provide insight into the differences observed due to OM in the dynamics and mechanism of the decomposition of ATP to ADP and HPO 4 2–, a central part of the power generation in cardiac muscle. We studied chemistry in the presence of the same three mutations to further elucidate the effect of OM, and its use in the treatment of cardiac disease.