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Identification of 1‐phenyl‐4‐cyano‐5‐aminopyrazoles as novel ecdysone receptor ligands by virtual screening, structural optimization, and biological evaluations
Author(s) -
Hu Xueping,
Ma Xiaojuan,
Cui Jialin,
Liu Haishan,
Zhu Bin,
Xie Jin,
Liang Pei,
Zhang Li
Publication year - 2021
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13772
Subject(s) - ecdysone , pharmacophore , virtual screening , plutella , in silico , ecdysone receptor , docking (animal) , combinatorial chemistry , chemistry , molecular mechanics , computational biology , stereochemistry , molecule , biology , biochemistry , organic chemistry , transcription factor , nuclear receptor , hormone , gene , ecology , lepidoptera genitalia , medicine , nursing
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.