# Molecular models to characterize actions of calcium sensitizing drugs

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $363,131

## Abstract

Project Summary / Abstract
Heart failure is a pressing problem in today’s society. Positive inotropic agents are needed in the
treatment of heart failure due to left ventricular systolic dysfunction. Many of the currently used drugs
(such as β-adrenergic agonists and phosphodiesterase III inhibitors) are ineffective in the long-term
since they are plagued with severe side effects. Calcium sensitizing agents are interesting alternative
drug candidates if they can cause a positive inotropic effect without associated side effects. One
possible target for calcium sensitizing drugs is cardiac troponin (cTn), a Ca2+-dependent switch,
activating and deactivating the myofilament leading to contraction and relaxation. Cardiac cTn
consists of three subunits: cTnC, cTnI and cTnT. Increasingly routine computational methods are
used to study cTn. However, there remains a critical need for development of novel and more precise
tools that expand understanding of molecular processes governing heart contraction in order to guide
targeted drug discovery studies. The main objective of this proposal is to develop novel
computational methods to predict and modulate calcium sensitization within cTnC. Results
from computational method advances will be verified experimentally and the experimental
results will drive additional method refinement. The proposed research is structured into three
main stages. We will use computer-aided drug design studies to find and experimentally verify novel
calcium sensitizing agents (Aim I) and then develop computational models to understand the
molecular processes in cTn that underlie the observed sensitizing effect with direct feedback to
experiments (Aims II and III). Method development work will focus on overcoming two main hurdles
faced by current computational models of cardiomyocyte contraction. Firstly, we will develop new
methodology to accurately predict calcium binding affinities to cTnC (Aim II). Based on strong
preliminary data, we hypothesize that this requires polarizable force fields, without which Ca2+
binding is not adequately modeled and oversimplified in molecular dynamics (MD) simulations.
Secondly, we will predict the degree to which drugs open up the cTnC-cTnI interface (Aim III). Based
on preliminary data, our hypothesis is that microsecond MD simulations and new methodology are
needed to determine the opening degree of the hydrophobic patch in drug-bound conformations.
Results from computational method advances will be verified experimentally and the experimental
results will drive additional method refinement and improve our initial drug discovery hits.

## Key facts

- **NIH application ID:** 10063891
- **Project number:** 5R01HL137015-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Steffen Lindert
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $363,131
- **Award type:** 5
- **Project period:** 2018-01-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10063891

## Citation

> US National Institutes of Health, RePORTER application 10063891, Molecular models to characterize actions of calcium sensitizing drugs (5R01HL137015-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10063891. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*