Computer-Aided Drug Discovery Approach Finds Calcium Sensitizer of Cardiac Troponin

Authors

  • Steffen Lindert,

    Corresponding author
    1. Department of Pharmacology, University of California San Diego, La Jolla, CA, USA
    2. NSF Center for Theoretical Biological Physics, La Jolla, CA, USA
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  • Monica X. Li,

    1. Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
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  • Brian D. Sykes,

    1. Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
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  • J. Andrew McCammon

    1. Department of Pharmacology, University of California San Diego, La Jolla, CA, USA
    2. NSF Center for Theoretical Biological Physics, La Jolla, CA, USA
    3. Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA, USA
    4. Department of Chemistry & Biochemistry, National Biomedical Computation Resource, University of California San Diego, La Jolla, CA, USA
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Abstract

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 combined computational structure-based virtual screening drug discovery methods and solution NMR titration assays to identify a novel calcium sensitizer 4-(4-(2,5-dimethylphenyl)-1-piperazinyl)-3-pyridinamine (NSC147866) which binds to cTnC and the cTnC-cTnI147–163 complex. Its presence increases the affinity of switch peptide to cTnC by approximately a factor of two. This action is comparable to that of known levosimendan analogues.

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