Targeting Troponin C with Small Molecules Containing Diphenyl Moieties: Calcium Sensitivity Effects on Striated...

Area of Science:

• Biochemistry
• Cardiovascular Science
• Pharmacology

Background:

• Heart failure is a major cause of death, stemming from disruptions in the cardiac muscle's contractile apparatus.
• Cardiac muscle contraction relies on calcium, regulated by the troponin protein complex (cTn), particularly the N-terminal domain of its calcium-binding subunit (cNTnC).
• There is a critical need for small molecules that boost calcium sensitivity to improve cardiac function without affecting systolic calcium concentrations.

Approach:

• Investigated the effects of a previously identified calcium-sensitizing molecule (ChemBridge compound 7930079) on force generation in cardiac trabeculae and slow skeletal muscle fibers.
• Utilized Gaussian accelerated molecular dynamics with NMR-derived structures to predict receptor conformations.
• Employed a rational computational strategy for lead optimization, focusing on lipophilic diphenyl moieties.

Key Points:

• The study evaluated a novel small molecule's impact on muscle force generation.
• Computational methods, including Gaussian accelerated molecular dynamics, were used to guide drug design.
• Three new low-affinity binders were identified, comparable in affinity to trifluoperazine.

Conclusions:

• Compound 16 emerged as the most potent calcium sensitizer, exhibiting an apparent affinity of 117 ± 17 μM.
• This research contributes to developing new therapeutic agents for heart failure by enhancing cardiac contractility.
• The findings highlight the potential of small molecules to modulate calcium sensitivity for improved heart function.