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.
Department of Chemistry, Seoul National University, Seoul, 151-747, Korea.
Minseob
M
Koh
Seung Bum
SB
Park
D000475:Alkenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020816:Amino Acid Motifs; D017076:Computer-Aided Design; D015195:Drug Design; D054314:Drug Inverse Agonism; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D011960:Receptors, Estrogen / Q000737:chemistry / Q000378:metabolism*
D000475:Alkenes; D047628:Estrogen Receptor alpha; D008024:Ligands; D011960:Receptors, Estrogen