Identification of 1‐phenyl‐4‐cyano‐5‐aminopyrazoles as novel ecdysone receptor ligands by virtual screening, structural optimization, and biological evaluations

Ecdysteroids initiate the molting process in insects by binding to the ecdysone receptor (EcR), which is a promising target for identifying insect growth regulators. This paper presents an in silico/in vitro screening procedure for identifying new EcR ligands. The three‐step virtual screening procedure uses a three‐dimensional pharmacophore model, docking and Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) rescoring routine. A novel hit ( VS14 ) with good binding activity against Plutella xylostella EcR was identified from a library of over 200,000 chemicals. Subsequently, the 1‐phenyl‐4‐cyano‐5‐aminopyrazole scaffold and twelve EcR ligands were synthesized. Their IC 50 values against Plutella xylostella EcR ranged from 0.64 to 23.21 μ m . Furthermore, a preliminary analysis of the structure–activity relationship for novel scaffolds provided a basis for designing new ligands with improved activity.