Evaluation of hydrogen bonds of ecdysteroids in the ligand-receptor interactions using a protein modeling system

The insect molting hormone, 20-hydroxyecdysone (20E) and its analogs (ecdysteroids) specifically bind to the ecdysone receptor. Previously, we synthesized various ecdysteroids containing the side chain moiety of ponasterone A (PonA), and measured the binding activity against Drosophila Kc cells to study the structure-activity relationship. Here we quantitatively analyzed the structure-activity relationship for the ligand binding of ecdysteroids including 20E and PonA. Since the hydrogen bonding (HB) is one of the important physicochemical properties for ligand binding to the ecdysteroid receptor, the number of possible HBs between the ligand molecule and the receptor was manually counted in the modeled ligand-receptor complex for all compounds. The construction of the ligand-receptor model was executed by the full-automatic modeling system (FAMS) in which calculation was done by simulated annealing. The binding potency of 15 ecdysteroids to Kc-cells were linearly correlated (r(2)=0.63) with the number of HBs which are observed between ligand and receptor molecule. Contribution of steric and electrostatic effects on the ligand-receptor binding was also examined using a three-dimensional quantitative structure-activity relationship (3-D QSAR), comparative molecular field analysis (CoMFA).