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BRIEF RESEARCH REPORT article

Front. Mol. Biosci.
Sec. Biological Modeling and Simulation
Volume 12 - 2025 | doi: 10.3389/fmolb.2025.1523932

Uncovering a Novel Binding Trench in ERRα: Insights from Molecular Simulations

Provisionally accepted
LAMEES HEGAZY LAMEES HEGAZY *
  • St. Louis College of Pharmacy, St. Louis, United States

The final, formatted version of the article will be published soon.

    Although Estrogen-related receptor α (ERRα) holds significant therapeutic potential for treating various disorders, developing selective agonists remains challenging due to the poor pharmacokinetics and limited selectivity of current ligands. This study presents unconstrained molecular dynamics simulations of ERRα bound to an agonist ligand, uncovering dynamic ligandbinding behavior as the ligand shifts between two orientations: one in the orthosteric pocket and another in a newly identified trench adjacent to this site. The free energy landscape reveals that both binding orientations are comparably populated, with an accessible transition pathway between them. The identification of this novel binding trench expands our understanding of ERRα's ligand-binding domain, offering new avenues for small-molecule drug discovery and selective modulation of ERRα activity.

    Keywords: molecular dynamics simualtions, ligand recognition, estrogen-related receptor (ERR), Drug Discovery, Novel binding trench, dynamic ligand binding

    Received: 06 Nov 2024; Accepted: 13 Jan 2025.

    Copyright: © 2025 HEGAZY. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: LAMEES HEGAZY, St. Louis College of Pharmacy, St. Louis, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.