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

Lukasz Szatkowski, Melissa L. Lynn, Teryn Holeman, Michael R. Williams, Anthony P. Baldo, Jil C Tardiff, Steven D Schwartz

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6492-6501
Number of pages10
JournalACS Omega
Volume4
Issue number4
DOIs
StatePublished - Apr 9 2019

Fingerprint

Molecular modeling
Molecules
Experiments
Docks
Animals
Repair
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

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. / Szatkowski, Lukasz; Lynn, Melissa L.; Holeman, Teryn; Williams, Michael R.; Baldo, Anthony P.; Tardiff, Jil C; Schwartz, Steven D.

In: ACS Omega, Vol. 4, No. 4, 09.04.2019, p. 6492-6501.

Research output: Contribution to journalArticle

@article{e8970d8861f447dfad9dc526ac433768,
title = "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",
abstract = "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.",
author = "Lukasz Szatkowski and Lynn, {Melissa L.} and Teryn Holeman and Williams, {Michael R.} and Baldo, {Anthony P.} and Tardiff, {Jil C} and Schwartz, {Steven D}",
year = "2019",
month = "4",
day = "9",
doi = "10.1021/acsomega.8b03340",
language = "English (US)",
volume = "4",
pages = "6492--6501",
journal = "ACS Omega",
issn = "2470-1343",
publisher = "American Chemical Society",
number = "4",

}

TY - JOUR

T1 - 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

AU - Szatkowski, Lukasz

AU - Lynn, Melissa L.

AU - Holeman, Teryn

AU - Williams, Michael R.

AU - Baldo, Anthony P.

AU - Tardiff, Jil C

AU - Schwartz, Steven D

PY - 2019/4/9

Y1 - 2019/4/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85064233440&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064233440&partnerID=8YFLogxK

U2 - 10.1021/acsomega.8b03340

DO - 10.1021/acsomega.8b03340

M3 - Article

AN - SCOPUS:85064233440

VL - 4

SP - 6492

EP - 6501

JO - ACS Omega

JF - ACS Omega

SN - 2470-1343

IS - 4

ER -