Key result
Computational approach identifies compound 16 as a novel troponin C calcium sensitizer with ~117 μM affinity.
Why the study?
Heart failure remains a leading cause of death, creating a need for small molecules that increase calcium sensitivity without altering systolic calcium concentration to strengthen cardiac function.
Computational modeling and in vitro testing identified novel small molecules, such as compound 16, that act as calcium sensitizers by targeting troponin C.
Hypothesis-generating for troponin C-targeted sensitization; leaves open in vivo efficacy in heart failure models.
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 systolic calcium concentration, thereby strengthening 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 led to the identification of three novel low affinity binders, which had similar binding affinities to known positive inotrope trifluoperazine. The most potent identified calcium sensitizer was compound 16 with an apparent affinity of 117 ± 17 μM .
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Hantz et al. (2023) studied Heart failure. ChemBridge compound 7930079 and novel diphenyl moiety compounds (e.g., compound 16) vs. Trifluoperazine was evaluated on Binding affinity. A rational computational approach identified compound 16 as a novel calcium sensitizer targeting troponin C with an apparent affinity of 117 ± 17 μM.
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