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

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

Nat Commun

Randall Centre for Cell and Molecular Biophysics; and British Heart Foundation Centre of Research Excellence, King's College London, London, SE1 1UL, United Kingdom.

Published: November 2023

AI Article Synopsis

Article 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.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10673995PMC
http://dx.doi.org/10.1038/s41467-023-43538-yDOI Listing

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