Discovery and MD Simulation of a Triterpenoid Zj7 as GR Modulator Targeting Non‐Classical GRE with Potent Anti‐Obesity Activity

Abstract Despite the potential of non‐classical glucocorticoid response element (GRE)‐selective glucocorticoid receptor (GR) modulators in biomedical sciences, progress has not yet been made. In this study, we discovered a first‐in‐class chemical modulator that selectively suppresses the transcriptional activity of the GR in a gene with a non‐classical GRE, but not with classical GREs. The orexigenic agouti‐related peptide ( Agrp )‐gene with a non‐classical GRE was chosen for this study. Similarity‐implemented virtual screening and rational modification of the structure of the initial hit compounds led to the identification of a pentacyclic natural triterpenoid, Zj7 (2‐ O‐trans‐p ‐coumaroylalphitolic acid). With this compound, we recently reported the verification of the orexigenic function and mechanism of action of GR in AgRP neurons. Herein, we describe the detailed discovery process leading to the identification of Zj7 and propose its molecular mode of action using molecular dynamics simulation.