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, remainsa leading cause of death. Cardiac muscle contraction is a calcium-dependentmechanism, 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 smallmolecules that increase calcium sensitivity without altering the systoliccalcium concentration, thereby strengthening the cardiac function.Here, we examined the effect of our previously identified calcium-sensitizingsmall molecule, ChemBridge compound 7930079, in the context of severalhomologous muscle systems. The effect of this molecule on force generationin isolated cardiac trabeculae and slow skeletal muscle fibers wasmeasured. Furthermore, we explored the use of Gaussian acceleratedmolecular dynamics in sampling highly predictive receptor conformationsbased on NMR-derived starting structures. Additionally, we took arational computational approach for lead optimization based on lipophilicdiphenyl moieties. This integrated structural-biochemical-physiologicalapproach led to the identification of three novel low-affinity binders,which had similar binding affinities to the known positive inotropetrifluoperazine. The most potent identified calcium sensitizer wascompound 16 with an apparent affinity of 117 & PLUSMN; 17 & mu;M.