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

Area of Science:

• Biochemistry
• Cardiovascular Biology
• Pharmacology

Background:

• Directly modulating cardiac myosin function is a key therapeutic strategy for heart disease and heart failure.
• Developing myosin-based therapeutics is challenging due to the absence of effective in vitro screening assays.
• Novel small molecules targeting cardiac myosin are needed to advance treatment options.

Purpose of the Study:

• To identify novel small molecule effectors of human β-cardiac myosin using artificial intelligence-based virtual high-throughput screening (vHTS).
• To characterize the mechanism of action and efficacy of identified compounds in cardiac muscle models.

Main Methods:

• Artificial intelligence-based virtual high-throughput screening (vHTS) to identify potential myosin inhibitors.
• Biochemical counter-screens to validate identified compounds.
• Biophysical characterization of lead compounds in isolated proteins and muscle fibers.
• Assessment of functional effects in isolated myofilaments and Langendorff-perfused hearts.

Main Results:

• vHTS identified novel small molecule effectors of human β-cardiac myosin.
• A novel chemical scaffold, 'F10', was identified as a cardiac-specific, low-micromolar myosin inhibitor.
• F10 stabilizes the biochemical (super-relaxed state) and structural (interacting heads motif) OFF states of cardiac myosin.
• F10 reduces force in isolated myofilaments and left ventricular pressure in perfused hearts.

Conclusions:

• F10 represents a novel chemical scaffold for cardiac myosin modulation.
• The identified compound demonstrates efficacy in stabilizing the myosin OFF state and reducing cardiac contractility.
• F10 serves as a tunable scaffold for developing a new class of myosin modulators for heart conditions.