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

ABSTRACT: 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 HPO₄^2-, 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.

SUBMITTER: Chakraborti A

PROVIDER: S-EPMC9830884 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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

Chakraborti Ananya A Tardiff Jil C JC Schwartz Steven D SD

The journal of physical chemistry. B 20221129 48

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 ...[more]

PMID: 36448224

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Project description:BackgroundMyocardial dysfunction is a major cause of poor outcomes in the post-cardiac arrest period. Omecamtiv mecarbil (OM) is a selective small molecule activator of cardiac myosin that prolongs myocardial systole and increases stroke volume without apparent effects on myocardial oxygen demand. OM administration is safe and improves cardiac function in patients with acute heart failure. Whether OM improves post-resuscitation myocardial dysfunction remains unclear. This study investigated the effect of OM treatment on post-resuscitation myocardial dysfunction and outcomes.Methods and resultsAdult male rats were resuscitated after 9.5 min of asphyxia-induced cardiac arrest. OM and normal saline was continuously intravenously infused after return of spontaneous circulation (ROSC) at 0.25 mg/kg/h for 4 h in the experimental group and control group, respectively (n = 20 in each group). Hemodynamic parameters were measured hourly and monitored for 4 h after cardiac arrest. Recovery of neurological function was evaluated by neurological functioning scores (0-12; favorable: 11-12) for rats 72 h after cardiac arrest. OM treatment prolonged left ventricular ejection time and improved post-resuscitation cardiac output. Post-resuscitation heart rate and left ventricular systolic function (dp/dt40) were not different between groups. Kaplan-Meier analysis showed non-statistically higher 72-h survival in the OM group (72.2% [13/18] and 58.8% [10/17], p = 0.386). The OM group had a higher chance of having favorable neurological outcomes in surviving rats 72 h after cardiac arrest (84.6% [11/13] vs. 40% [4/10], p = 0.026). The percentage of damaged neurons was lower in the OM group in a histology study at 72 h after cardiac arrest (55.5±2.3% vs. 76.2±10.2%, p = 0.004).ConclusionsOM treatment improved post-resuscitation myocardial dysfunction and neurological outcome in an animal model. These findings support further pre-clinical studies to improve outcomes in post-cardiac arrest care.

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

Publications

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

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