Perspectives of a myosin motor activator agent with increased selectivity

Nánási, Péter and Komáromi, István and Almássy, János (2018) Perspectives of a myosin motor activator agent with increased selectivity. CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY, 96. pp. 676-680. ISSN 0008-4212

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Abstract

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 3 phase displaying promising clinical performance. However, omecamtiv mecarbil is not selective to myosin, since it readily binds to and activates cardiac ryanodine receptors (RyR-2), an effect that may cause complications is 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 in order to select the structure which 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 µM. 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.

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