Calcium-dependent cardiac muscle contraction is regulated by the troponin protein complex (cTn), which consists of three subunits: troponin T (cTnT) which anchors the protein complex to tropomyosin, troponin I (cTnI) which inhibits actomyosin interaction, and troponin C (cTnC) the calcium binding subunit. cTnC is a dumbbell-shaped protein with globular terminal domains linked by a long central helix. The C-terminal domain, the structural domain of the cTnC subunit, facilitates key interactions related to anchoring the protein to the remaining cTn complex and the thin filament. The N-terminal domain is frequently referred to as the regulatory domain, due to the conformational change the complex undergoes once a calcium ion binds to site II. The conformational change results in the exposure of the cNTnC hydrophobic patch which promotes binding of the cTnI switch peptide, thereby facilitating disassociation of cTnI from actin. This hydrophobic patch has been a target of substantial interest for the treatment of congestive heart failure via drug-like small molecules. Compounds that increase Ca<sup>2+</sup> sensitivity without altering the concentration of systolic Ca<sup>2+</sup> are of particular interest. In a previous study, we have identified ChemBridge compound 7930079 with an apparent binding affinity of 1.45 ± 0.09 μM. To date, this is one of the most potent and high affinity binders. In this work, we further characterize the calcium sensitizing effects of 7930079 in several muscle fibers. Additionally, we utilize the knowledge of high affinity calcium sensitizers for further virtual screenings to identified novel sensitizing small molecules.

Identification of additional hydrophobic patch binders in cardiac troponin C

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