Elgendy, B. | Search bioRxiv

bioRxiv2022

A Synthetic ERRα Agonist Induces an Acute AerobicExercise Response and Enhances Exercise Capacity

Repetitive physical exercise induces physiological adaptations in skeletal muscle that improves exercise performance and is effective for the prevention and treatment of several diseases. Here we report the identification of a synthetic agonist for the orphan nuclear receptor ERR (estrogen receptor-related receptor ), SLU-PP-332, that activates an acute aerobic exercise genetic program in skeletal muscle in an ERR-dependent manner. SLU-PP-332 increases mitochondrial function and cellular respiration consistent with induction of this genetic program. When administered to mice, SLU-PP-332 increased the type IIa oxidative skeletal muscle fibers and enhanced exercise endurance. These data indicate the feasibility of targeting ERR for development of compounds that act as exercise mimetics that may be effective in treatment of numerous metabolic disorders and to improve muscle function in the aging.

pharmacology and toxicology↗

bioRxiv2021

Distinct REV-ERBα Conformational State Predicted by GaMD Simulations Leads to the Structure-Based Discovery of Novel REV-ERBα Antagonist

REV-ERB is a nuclear hormone receptor that plays important role in the regulation of many physiological processes such as circadian clock regulation, inflammation, and metabolism. Despite its importance, few chemical tools are available to study this receptor. In addition, there is no available X-ray crystal structures of REV-ERB bound with synthetic ligands, hampering the development of targeted therapeutics. SR8278 is the only identified synthetic antagonist of REV-ERB. We have performed Gaussian accelerated molecular dynamics (GaMD) simulations to sample the binding pathway of SR8278 and associated conformational changes to REV-ERB. The simulations revealed a novel and more energetically favorable conformational state than the starting conformation. The new conformation allows ligand binding to the orthosteric binding site in a specific orientation. This state is reached after a tryptophan (Trp436) rotameric switch coupled with H3-H6 distance change. We used the newly identified GaMD conformational state in structure-based virtual screening of one million compounds library which led to the identification of novel REV-ERB antagonist. This study is the first that demonstrates a synthetic ligand binding pathway to REV-ERB, which provided important insights into the REV-ERB functional mechanism and lead to the discovery of novel REV-ERB antagonists. This study further emphasizes the power of computational chemistry methods in advancing drug discovery research.

biophysics↗