Clinical treatment of heart failure is still not fully solved. A novel class of 
agents, the myosin motor activators, acts directly on cardiac myosin resulting 
in an increased force generation and prolongation of contraction. Omecamtiv 
mecarbil, the lead molecule of this group, is now in human phase 3 displaying 
promising clinical performance. However, omecamtiv mecarbil is not selective to 
myosin, because it readily binds to and activates cardiac ryanodine receptors 
(RyR-2), an effect that may cause complications in case of overdose. In this 
study, in silico analysis was performed to investigate the docking of omecamtiv 
mecarbil and other structural analogues to cardiac myosin heavy chain and RyR-2 
to select the structure that has a higher selectivity to myosin over RyR-2. In 
silico docking studies revealed that omecamtiv mecarbil has comparable affinity 
to myosin and RyR-2: the respective Kd values are 0.60 and 0.87 μmol/L. Another 
compound, CK-1032100, has much lower affinity to RyR-2 than omecamtiv mecarbil, 
while it still has a moderate affinity to myosin. It was concluded that further 
research starting from the chemical structure of CK-1032100 may result a better 
myosin activator burdened probably less by the RyR-2 binding side effect. It 
also is possible, however, that the selectivity of omecamtiv mecarbil to myosin 
over RyR-2 cannot be substantially improved, because similar moieties seem to be 
responsible for the high affinity to both myosin and RyR-2.