# A New Paradigm to Incorporate Protein Dynamics into Targeted Small Molecule Design for Sarcomeric Cardiomyopathies: A Proof of Concept for Thin Filament Therapeutics

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2021 · $465,498

## Abstract

The goal of the research program described in this application is the development of a new paradigm in
therapeutic chemical design for small molecules to target Hypertrophic Cardiomyopathy (HCM.) Though the
disease afflicts roughly 1 in 500 people, and can at times have devastating health consequences, current
treatment options remain limited and are largely palliative. With the expansion of genetic testing in the past
decade, patients are now identified at earlier stages of the disorder (genotype +, phenotype - ), raising the
motivation for directly targeting the primary biophysical disease mechanism prior to the onset of overt disease
in order to change the natural history of the disorder. We have developed a robust integrative program aimed
at understanding disease mechanism across multiple levels of resolution, from computational models to in vitro
systems, to eventual in vivo mouse models of disease. We here propose to identify small molecule modulators
targeted at initial molecular insult caused by mutation. Our goal is not the generation of a specific medical
treatment, but the development, rather, of a novel, high-throughput approach through this ambitious proof of
concept research program. We have identified several general categories of thin filament mutations that are
closely linked to both the structure and dynamics of myofilament activation, and how the components interact
with each other to create the allosterically regulated cardiac thin filament. Both the overall design of the
program is highly innovative in the creation of a new therapeutic development paradigm based on physics,
chemistry, and biology, and the integrated methods themselves. The program will be implemented via the
following 3 Specific Aims:
Aim 1: To utilize our all-atom, explicitly solvated cardiac thin filament model as a platform to identify small
molecule compounds that bind the thin filament and increase the flexibility of the TNT1 C-terminal linker
domain and to fully validate the effects of this modulation on a known cTnT HCM mutation in vitro and in vivo.
Aim 2: To screen for, design and test novel small molecule modulators that target the dynamics of the cTnI N-
terminus in silico and validate and test their effects on the kinetics of Ca2+ dissociation from cTnC in vitro and
in vivo.
Aim 3: To leverage our recently refined, explicitly solvated structure of the cardiac tropomyosin overlap
domain of the thin filament to screen for novel modulators of overlap dynamics, specifically targeting hydrogen
bonding potential or nonlocal effects as a mediator of flexibility and validating these effects in vitro and in vivo.

## Key facts

- **NIH application ID:** 10067566
- **Project number:** 5R01HL137375-04
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** STEVEN D SCHWARTZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $465,498
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067566

## Citation

> US National Institutes of Health, RePORTER application 10067566, A New Paradigm to Incorporate Protein Dynamics into Targeted Small Molecule Design for Sarcomeric Cardiomyopathies: A Proof of Concept for Thin Filament Therapeutics (5R01HL137375-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10067566. Licensed CC0.

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