2023/11/24 by Priyanka Parijat, Seetharamaiah Attili, Zoe Hoare +3 · 1 voice
Biochemistry, Genetics and Molecular Biology · Engineering · Medicine · #Cardiomyopathy and Myosin Studies #Integrated Circuits and Semiconductor Failure Analysis #Viral Infectious Diseases and Gene Expression in Insects
paper · pdf · doi:10.1038/s41467-023-43538-y
openalex publication_date 2023/11/24 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
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.