Targeting Troponin C with Small Molecules Containing Diphenyl Moieties: Calcium Sensitivity Effects on Striated Muscles and Structure–Activity Relationship

Despite large investments from academia and industry,
heart failure,
which results from a disruption of the contractile apparatus, remains
a leading cause of death. Cardiac muscle contraction is a calcium-dependent
mechanism, which is regulated by the troponin protein complex (cTn)
and specifically by the N-terminal domain of its calcium-binding subunit
(cNTnC). There is an increasing need for the development of small
molecules that increase calcium sensitivity without altering the systolic
calcium concentration, thereby strengthening the cardiac function.
Here, we examined the effect of our previously identified calcium-sensitizing
small molecule, ChemBridge compound 7930079, in the context of several
homologous muscle systems. The effect of this molecule on force generation
in isolated cardiac trabeculae and slow skeletal muscle fibers was
measured. Furthermore, we explored the use of Gaussian accelerated
molecular dynamics in sampling highly predictive receptor conformations
based on NMR-derived starting structures. Additionally, we took a
rational computational approach for lead optimization based on lipophilic
diphenyl moieties. This integrated structural–biochemical–physiological
approach led to the identification of three novel low-affinity binders,
which had similar binding affinities to the known positive inotrope
trifluoperazine. The most potent identified calcium sensitizer was
compound 16 with an apparent affinity of 117 ± 17 μM.