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

Area of Science:

• Biochemistry
• Physiology
• Computational Biology

Background:

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

Purpose of the Study:

• To investigate the calcium-sensitizing effects of ChemBridge compound 7930079 in homologous muscle systems.
• To optimize lead compounds for enhanced calcium sensitivity using computational and structural approaches.
• To identify novel small molecules for potential heart failure treatment.

Main Methods:

• Tested ChemBridge compound 7930079's effect on force generation in isolated cardiac trabeculae and slow skeletal muscle fibers.
• Employed Gaussian accelerated molecular dynamics with NMR-derived structures to predict receptor conformations.
• Utilized a rational computational approach for lead optimization focusing on lipophilic diphenyl moieties.

Main Results:

• The study evaluated a previously identified calcium-sensitizing molecule, ChemBridge compound 7930079.
• An integrated structural-biochemical-physiological approach identified three novel low-affinity binders.
• Compound 16 emerged as the most potent calcium sensitizer, with an apparent affinity of 117 ± 17 μM, comparable to trifluoperazine.

Conclusions:

• The identified compounds demonstrate potential as positive inotropes for treating heart failure.
• The study highlights the efficacy of an integrated computational and experimental approach for drug discovery in cardiovascular disease.
• Novel calcium sensitizers were discovered, offering a promising avenue for improving cardiac contractility.