TY - JOUR
T1 - Insights into the Mechanism of the Cardiac Drug Omecamtiv Mecarbil A Computational Study
AU - Chakraborti, Ananya
AU - Tardiff, Jil C.
AU - Schwartz, Steven D.
N1 - Funding Information:
This research was supported by the National Institute of Health grant R01HL107046 to J.C.T. and S.D.S. All computer simulations were performed on a Lenovo NeXtScale nx360 M5 supercomputer at the University of Arizona High Performance Computing Center.
Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/12/8
Y1 - 2022/12/8
N2 - 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 HPO42-, 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.
AB - 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 HPO42-, 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.
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U2 - 10.1021/acs.jpcb.2c06679
DO - 10.1021/acs.jpcb.2c06679
M3 - Article
C2 - 36448224
AN - SCOPUS:85143518700
SN - 1520-6106
VL - 126
SP - 10069
EP - 10082
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
IS - 48
ER -