Proof of Principle that Molecular Modeling Followed by a Biophysical Experiment Can Develop Small Molecules that Restore Function to the Cardiac Thin Filament in the Presence of Cardiomyopathic Mutations
Lynn, Melissa L.
Williams, Michael R.
Baldo, Anthony P.
Tardiff, Jil C.
Schwartz, Steven D.
AffiliationUniv Arizona, Dept Med
Univ Arizona, Dept Chem & Biochem
MetadataShow full item record
PublisherAMER CHEMICAL SOC
CitationSzatkowski, L., Lynn, M. L., Holeman, T., Williams, M. R., Baldo, A. P., Tardiff, J. C., & Schwartz, S. D. (2019). Proof of Principle that Molecular Modeling Followed by a Biophysical Experiment Can Develop Small Molecules that Restore Function to the Cardiac Thin Filament in the Presence of Cardiomyopathic Mutations. ACS Omega, 4(4), 6492-6501.
RightsCopyright © 2019 American Chemical Society. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at email@example.com.
AbstractThis 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.
NoteOpen access journal
VersionFinal published version