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 IC50 values against Plutella xylostella EcR ranged from 0.64 to 23.21 μm. Furthermore, a preliminary analysis of the structure-activity relationship for novel scaffolds provided a basis for designing new ligands with improved activity.