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

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

  • Nat Commun. 2023 Nov 24;14(1):7692. doi: 10.1038/s41467-023-43538-y.
Priyanka Parijat 1,  Seetharamaiah Attili 1,  Zoe Hoare 2,  Michael Shattock 2,  Victor Kenyon 3,  Thomas Kampourakis 4
Affiliations

Affiliations

  • 1 Randall Centre for Cell and Molecular Biophysics; and British Heart Foundation Centre of Research Excellence, King's College London, London, SE1 1UL, United Kingdom.
  • 2 School of Cardiovascular and Metabolic Medicine and Sciences; Rayne Institute and British Heart Foundation Centre of Research Excellence, King's College London, London, SE5 9NU, United Kingdom.
  • 3 Atomwise Inc., San Francisco, CA, USA.
  • 4 Randall Centre for Cell and Molecular Biophysics; and British Heart Foundation Centre of Research Excellence, King's College London, London, SE1 1UL, United Kingdom. thomas.kampourakis@kcl.ac.uk.
PMID: 38001148 DOI: 10.1038/s41467-023-43538-y
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.

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