Abstract
Defects in the contractile machinery can lead to heart failure. Weakened contraction of the heart will lead to diminished blood supply of the organs in the human body. Thus, in the fight against heart failure, therapeutics that have the ability to increase the contractile power of the heart are urgently needed. One possible route of action to improve heart contractile power is increasing the calcium sensitivity of the thin filament. From a pharmaceutical standpoint, calcium sensitizers have the distinct advantage of not altering cardiomyocyte calcium levels and thus have lower potential for side effects. Small chemical molecules have been shown to bind to the interface between cTnC and the cTnI switch peptide and exhibit calcium sensitizing properties, possibly by stabilizing cTnC in an open conformation. Building on existing structural data of a known calcium sensitizer bound to cardiac troponin, we devised a combined computational and experimental drug discovery approach. We used Molecular Dynamics to sample a range of troponin structure conformations and accounted for receptor flexibility by running virtual screens into several conformational states. The most promising compounds were then tested using solution NMR titration assays. We were able to identify a novel calcium sensitizer 4-(4-(2,5-dimethylphenyl)-1-piperazinyl)-3-pyridinamine (NCI147866) which binds to cTnC and the cTnC-cTnI147-163 complex. Its presence increased the affinity of switch peptide to cTnC by approximately a factor of two. This action was comparable to that of known levosimendan analogues and served as an excellent starting point for targeted compound improvement aimed at higher affinity and calcium sensitization.
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