Chemistry Department, Faculty of Science, Benha University, Benha 13518, Egypt.
Department of Pharmaceutical and Administrative Sciences, St. Louis College of Pharmacy, St. Louis, MO 63110, USA; Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO 63110, USA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt.
Bioorg Chem. 2020 Sep;102:104079. doi: 10.1016/j.bioorg.2020.104079. Epub 2020 Jul 7.
Estrogen Related Receptors (ERRs) are key regulators of energy homeostasis and play important role in the etiology of metabolic disorders, skeletal muscle related disorders, and neurodegenerative diseases. Among the three ERR isoforms, ERRα emerged as a potential drug target for metabolic and neurodegenerative diseases. Although ERRβ/γ selective agonist chemical tools have been identified, there are no chemical tools that effectively target ERRα agonism. We successfully engineered high affinity ERRα agonism into a chemical scaffold that displays selective ERRβ/γ agonist activity (GSK4716), providing novel ERRα/β/γ pan agonists that can be used as tools to probe the physiological roles of these nuclear receptors. We identified the structural requirements to enhance selectivity toward ERRα. Molecular modeling shows that our novel modulators have favorable binding modes in the LBP of ERRα and can induce conformational changes where Phe328 that originally occupies the pocket is dislocated to accommodate the ligands in a rather small cavity. The best agonists up-regulated the expression of target genes PGC-1α and PGC-1β, which are necessary to achieve maximal mitochondrial biogenesis. Moreover, they increased the mRNA levels of PDK4, which play an important role in energy homeostasis.
雌激素相关受体（ERRs）是能量平衡的关键调节剂，在代谢紊乱、骨骼肌相关疾病和神经退行性疾病的发病机制中发挥重要作用。在这三种 ERR 同工型中，ERRα 作为代谢和神经退行性疾病的潜在药物靶点而出现。尽管已经确定了 ERRβ/γ 选择性激动剂化学工具，但没有有效的靶向 ERRα激动剂的化学工具。我们成功地将高亲和力 ERRα激动作用工程化到一种化学支架中，该支架显示出选择性的 ERRβ/γ 激动剂活性（GSK4716），提供了新型的 ERRα/β/γ 泛激动剂，可作为研究这些核受体生理作用的工具。我们确定了增强对 ERRα 选择性的结构要求。分子建模表明，我们的新型调节剂在 ERRα 的 LBP 中有良好的结合模式，可以诱导构象变化，使原本占据口袋的 Phe328 移位，以适应较小的配体腔。最佳激动剂上调了靶基因 PGC-1α 和 PGC-1β 的表达，这些基因对于实现最大的线粒体生物发生是必要的。此外，它们增加了 PDK4 的 mRNA 水平，PDK4 在能量平衡中起着重要作用。
