I. Design and synthesis of estrogen receptor gene switches. II. Design and synthesis of estrogen receptor ligands occupying an auxiliary binding pocket

摘要

The estrogen receptor (ER) is ligand-regulated nuclear hormone receptor and an important therapeutic target for breast cancer, hormone replacement therapy, contraception, and osteoporosis. Novel organic cores have been identified and developed as possible estrogen pharmaceuticals. The x-ray structures of both estrogen receptor subtypes bound to unique ligands provide a way to interpret, improve, and/or design estrogen ligands using computer modeling. Novel synthetic estrogen ligands were designed using computer modeling to occupy a solvent channel present in all of the ER crystal structures, although those ligands bound poorly to the estrogen receptor. Also, single mutations of ER residues near the ligand binding pocket were evaluated using modeling to predict the size and shape of the mutated binding pocket that would not bind estradiol. Ligands were designed, synthesized, and tested using a yeast two-hybrid assay to activate the mutated receptor to near wild type activity and create a novel gene switch.