Discovery of a novel cardiac-specific myosin modulator using artificial intelligence-based virtual screening
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-...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-43538-y |
| _version_ | 1797452143697854464 |
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| author | Priyanka Parijat Seetharamaiah Attili Zoe Hoare Michael Shattock Victor Kenyon Thomas Kampourakis |
| author_facet | Priyanka Parijat Seetharamaiah Attili Zoe Hoare Michael Shattock Victor Kenyon Thomas Kampourakis |
| author_sort | Priyanka Parijat |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T15:04:31Z |
| format | Article |
| id | doaj.art-fdb3305c07434d8c93e33d876a8dec58 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-09T15:04:31Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-fdb3305c07434d8c93e33d876a8dec582023-11-26T13:46:23ZengNature PortfolioNature Communications2041-17232023-11-0114111410.1038/s41467-023-43538-yDiscovery of a novel cardiac-specific myosin modulator using artificial intelligence-based virtual screeningPriyanka Parijat0Seetharamaiah Attili1Zoe Hoare2Michael Shattock3Victor Kenyon4Thomas Kampourakis5Randall Centre for Cell and Molecular Biophysics; and British Heart Foundation Centre of Research Excellence, King’s College LondonRandall Centre for Cell and Molecular Biophysics; and British Heart Foundation Centre of Research Excellence, King’s College LondonSchool of Cardiovascular and Metabolic Medicine and Sciences; Rayne Institute and British Heart Foundation Centre of Research Excellence, King’s College LondonSchool of Cardiovascular and Metabolic Medicine and Sciences; Rayne Institute and British Heart Foundation Centre of Research Excellence, King’s College LondonAtomwise Inc.Randall Centre for Cell and Molecular Biophysics; and British Heart Foundation Centre of Research Excellence, King’s College LondonAbstract 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.https://doi.org/10.1038/s41467-023-43538-y |
| spellingShingle | Priyanka Parijat Seetharamaiah Attili Zoe Hoare Michael Shattock Victor Kenyon Thomas Kampourakis Discovery of a novel cardiac-specific myosin modulator using artificial intelligence-based virtual screening Nature Communications |
| title | Discovery of a novel cardiac-specific myosin modulator using artificial intelligence-based virtual screening |
| title_full | Discovery of a novel cardiac-specific myosin modulator using artificial intelligence-based virtual screening |
| title_fullStr | Discovery of a novel cardiac-specific myosin modulator using artificial intelligence-based virtual screening |
| title_full_unstemmed | Discovery of a novel cardiac-specific myosin modulator using artificial intelligence-based virtual screening |
| title_short | Discovery of a novel cardiac-specific myosin modulator using artificial intelligence-based virtual screening |
| title_sort | discovery of a novel cardiac specific myosin modulator using artificial intelligence based virtual screening |
| url | https://doi.org/10.1038/s41467-023-43538-y |
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