# Comprehensive understanding about the binding of estrogen-related receptor alpha (ERR-α) to inverse agonists with the first-principles based theoretical methods

> **NIH NIH R16** · ALBANY STATE UNIVERSITY · 2024 · $131,616

## Abstract

Comprehensive understanding about the binding of estrogen-related receptor alpha (ERR-α) to inverse
agonists with the first-principles based theoretical methods
ERR is one of three estrogen-related receptors (ERRs: ERR,- and -) that act as ligand-dependent transcription factors
and share common target genes. Substantial expression of ERR was found in a few types of breast cancers, and ERR
has thus been identified as a new target for breast cancer therapy. Breast cancers have become the most common
cancers diagnosed in the United States and one of the leading cause of cancer deaths in women. Therefore, it is urgent to
develop targeted therapy approaches for breast cancer treatment. A few classes of ERR inverse agonists were reported to
inhibit tumor development and progression by disrupting the interaction of ERR with their coactivators (PGC-1 and
PGC-1). The crystal structure for the complex ERR and an inverse agonist compound 1 (1-p-tolyl-1H-indol-3-ylmethyl-
amine, the most studied inverse agonist) reveals the conformation change as compared with active apo-ERR in the absence
of compound 1, and illustrates the major residues in the ligand binding pocket (LBP). However, the quantitative binding
affinities for the key residues with the inverse agonist are unknown, and the binding free energy for ERR/compound 1
predicted by previous theoretical methods is far from the experimental one. Although the inverse agonist
(thiadiazoleacrylamide, XCT790) and a few others also show strong inhibitory effects on the transcriptional activity of
ERR, the crystal structures for the complexes of these inverse agonists with ERRα are still unavailable, which considerably
limits an understanding about the mechanism by which these inverse agonists bind to ERRα, and inhibit the coactivation of
ERRα and PGC-1.
 Overall, the binding mechanism of ERR to the potential inverse agonists has not been well understood in terms
of binding modes and thermodynamics, and the hot spot residues that play an important role in the binding have not been
well defined. On the basis of our preliminary study we hypothesized that a) a potential inverse agonist needs to strongly
interact with the residues of H3, H5, H6/H7 loop, and H11 helix in the ligand binding domain (LBD) through hydrophobic
and hydrogen bonding. b) it is essential for an effective inverse agonist to strongly bind with the aromatic ring cluster
consisting of Phe328(H3), Phe495(H11), and Phe382(H5/H6 loop) as well as Leu500. The first-principles-based theoretical
methods such as molecular dynamics (MD) simulation and binding affinity calculations are able to provide meaningful
insights into the binding mechanism of ERR to the inverse agonists. Using large scale MD simulation with the updated
force fields and a robust binding free energy strategy, the major goal of the project therefore is to gain a comprehensive
understanding about the binding between ERR and a few inverse agonists in terms of binding mo...

## Key facts

- **NIH application ID:** 10850193
- **Project number:** 1R16GM153664-01
- **Recipient organization:** ALBANY STATE UNIVERSITY
- **Principal Investigator:** Yixuan Wang
- **Activity code:** R16 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $131,616
- **Award type:** 1
- **Project period:** 2024-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10850193

## Citation

> US National Institutes of Health, RePORTER application 10850193, Comprehensive understanding about the binding of estrogen-related receptor alpha (ERR-α) to inverse agonists with the first-principles based theoretical methods (1R16GM153664-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10850193. Licensed CC0.

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