Key result
A coupled computational and experimental approach identified candidate small molecules capable of repairing biophysical alterations in the cardiac thin filament caused by genetic mutations.
Why the study?
Hypertrophic and dilated cardiomyopathies caused by mutation are initially biophysical in nature, motivating an approach to design small molecules that correct the biophysical insult prior to irreversible cardiac damage.
Can computationally designed small molecules restore biophysical function to the cardiac thin filament in the presence of cardiomyopathic mutations?
Can computationally designed small molecules restore biophysical function to the cardiac thin filament in the presence of cardiomyopathic mutations?
This proof-of-concept study demonstrates that a coupled computational and experimental approach can identify small molecules capable of correcting biophysical defects in cardiac thin filaments caused by cardiomyopathic mutations.
Does not support clinical use; leaves open translation of candidate molecules to in vivo cardiomyopathic models.
This article reports a coupled computational experimental approach to design small molecules aimed at targeting genetic cardiomyopathies. We begin with a fully atomistic model of the cardiac thin filament. To this we dock molecules using accepted computational drug binding methodologies. The candidates are screened for their ability to repair alterations in biophysical properties caused by mutation. Hypertrophic and dilated cardiomyopathies caused by mutation are initially biophysical in nature, and the approach we take is to correct the biophysical insult prior to irreversible cardiac damage. Candidate molecules are then tested experimentally for both binding and biophysical properties. This is a proof of concept study-eventually candidate molecules will be tested in transgenic animal models of genetic (sarcomeric) cardiomyopathies.
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Szatkowski et al. (2019) studied Genetic cardiomyopathies. Computationally designed small molecules was evaluated on Binding and biophysical properties. A coupled computational and experimental approach identified candidate small molecules capable of repairing biophysical alterations in the cardiac thin filament caused by genetic mutations.
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