# Investigation and Targeting of Alternate Binding Site in ERRα

> **NIH NIH R21** · ST. LOUIS COLLEGE OF PHARMACY · 2022 · $193,888

## Abstract

Abstract
The World Health Organization announced a marked increase in patients with diabetes; from 108
million in 1980 to 422 million in 2014. Diabetes causes severe complications including blindness,
heart attacks and lower limb amputation with an estimated 1.5 million deaths annually caused by
diabetes. Therefore, there is growing interest in identifying novel drug targets and alternative
therapeutics approaches. Estrogen-related receptor α (ERRα) is a nuclear hormone receptor that
regulate gene expressions related to anti-inflammatory activities, oxidative phosphorylation,
biogenesis and fatty acid metabolism. Large body of data suggest ERRα as a promising therapeutic
target in treating metabolic disorders, such as type 2 diabetes and metabolic syndrome. The
identification of ERRα selective small molecule agonists would be valuable chemical probes and
pharmacological tools to further explore the role of ERRα in diabetes. However, existing ERRα
agonists lack in vivo potency and selectivity that are required for their use as chemical probes. In
addition, there are no X-ray crystal structures available for ERRα bound agonists, which hindered
the discovery of specific ERRα agonists. Understanding the molecular basis of agonist ligand
binding to ERRα is crucial for identification and optimization of novel potent and specific agonists.
Initial preliminary studies using molecular dynamics simulations, revealed the presence of novel
alternate binding site in ERRα. Targeting this alternate site holds premise for discovery of novel
ERRα agonists. We propose two specific aims to be done in two phases: 1) Investigation of the
mechanism of agonist ligand binding to ERRα orthosteric and allosteric sites using a combination of
computational and experimental approaches. This step is essential to characterize low energy state
structural ensembles favouring agonist binding to ERRα. 2) Implementation of computer-based drug
design approaches such as structure-based virtual screening for discovery of new molecular
scaffolds that bind and selectively activate ERRα. These aims will provide novel, first in class ligands
that selectively activate ERRα and can be used as chemical probes for investigation of their role in
diabetes in future grant proposals.

## Key facts

- **NIH application ID:** 10432870
- **Project number:** 1R21DK132605-01
- **Recipient organization:** ST. LOUIS COLLEGE OF PHARMACY
- **Principal Investigator:** Lamees Hegazy
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $193,888
- **Award type:** 1
- **Project period:** 2022-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10432870

## Citation

> US National Institutes of Health, RePORTER application 10432870, Investigation and Targeting of Alternate Binding Site in ERRα (1R21DK132605-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10432870. Licensed CC0.

---

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