Computer-aided design and synthesis of tetra-aryl-substituted alkenes and their bioevaluation as a selective modulator of estrogen-related receptor γ.

This study reports on a translational exercise in computer-aided rational drug design, chemical synthesis, and bioevaluation using a cell-based reporter gene assay, pursued exclusively for the development of specific estrogen-related receptor γ (ERR γ) inverse agonists with selectivity over estrogen receptor α (ER α). We designed and synthesized a 9-membered small-molecule collection, which has, as the key molecular framework, tetra-aryl-substituted alkene derived from 4-hydroxytamoxifen (4-OHT), a known ERR γ inverse agonist and antagonist of ER α. Although we could not achieve a more potent inverse agonist than GSK5182 from our compound collection, we demonstrated a reasonable correlation between the in silico docking simulation and biological data of transcriptional regulation on nuclear receptors. Therefore, we suggest that structural information regarding proteins-of-interest provides a novel insight into the rational design of new therapeutic agents and that the utilization of docking simulation as a preliminary filtering tool might be a useful option for medicinal chemists or chemical biologists.