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Discovery of a novel cardiac-specific myosin modulator using artificial intelligence-based virtual screening

Author

Listed:
  • Priyanka Parijat

    (King’s College London)

  • Seetharamaiah Attili

    (King’s College London)

  • Zoe Hoare

    (King’s College London)

  • Michael Shattock

    (King’s College London)

  • Victor Kenyon

    (Atomwise Inc.)

  • Thomas Kampourakis

    (King’s College London)

Abstract

Direct modulation of cardiac myosin function has emerged as a therapeutic target for both heart disease and heart failure. However, the development of myosin-based therapeutics has been hampered by the lack of targeted in vitro screening assays. In this study we use Artificial Intelligence-based virtual high throughput screening (vHTS) to identify novel small molecule effectors of human β-cardiac myosin. We test the top scoring compounds from vHTS in biochemical counter-screens and identify a novel chemical scaffold called ‘F10’ as a cardiac-specific low-micromolar myosin inhibitor. Biochemical and biophysical characterization in both isolated proteins and muscle fibers show that F10 stabilizes both the biochemical (i.e. super-relaxed state) and structural (i.e. interacting heads motif) OFF state of cardiac myosin, and reduces force and left ventricular pressure development in isolated myofilaments and Langendorff-perfused hearts, respectively. F10 is a tunable scaffold for the further development of a novel class of myosin modulators.

Suggested Citation

  • Priyanka Parijat & Seetharamaiah Attili & Zoe Hoare & Michael Shattock & Victor Kenyon & Thomas Kampourakis, 2023. "Discovery of a novel cardiac-specific myosin modulator using artificial intelligence-based virtual screening," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43538-y
    DOI: 10.1038/s41467-023-43538-y
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    References listed on IDEAS

    as
    1. Michael S. Woody & Michael J. Greenberg & Bipasha Barua & Donald A. Winkelmann & Yale E. Goldman & E. Michael Ostap, 2018. "Positive cardiac inotrope omecamtiv mecarbil activates muscle despite suppressing the myosin working stroke," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    2. Thomas Kampourakis & Malcolm Irving, 2021. "The regulatory light chain mediates inactivation of myosin motors during active shortening of cardiac muscle," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    3. Julien Robert-Paganin & Daniel Auguin & Anne Houdusse, 2018. "Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    Full references (including those not matched with items on IDEAS)

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