ArticleNature communications2023
Discovery of a novel cardiac-specific myosin modulator using artificial intelligence-based virtual screening.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
4 citing papers in PubMed, 10 citations in OpenAlex.
- Small Molecule Inhibitors ofInternational journal of molecular sciences · 2024Article
- Synthesis and Evaluation of 1,3-Disubstituted Imidazolidine-2,4,5-triones as Inhibitors of Pyruvate Carboxylase.ACS medicinal chemistry letters · 2024Article
- Intracellular Allosteric Antagonist of the Olfactory Receptor OR51E2.Molecular pharmacology · 2024Article
- Computer-Selected Antiviral Compounds: Assessing In Vitro Efficacies against Rift Valley Fever Virus.Viruses · 2024Article
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Authors and funding
6 authors at 2 institutions in 3 countries.
Funding
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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Registered trials
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