肌球蛋白
心肌
肌丝
细胞生物学
虚拟筛选
脚手架
药物发现
化学
计算生物学
生物
生物物理学
生物化学
医学
生物医学工程
解剖
作者
Priyanka Parijat,Seetharamaiah Attili,Zoe Hoare,Michael J. Shattock,Victor Kenyon,Thomas Kampourakis
标识
DOI:10.1038/s41467-023-43538-y
摘要
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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