Identification of 1‐phenyl‐4‐cyano‐5‐aminopyrazoles as novel ecdysone receptor ligands by virtual screening, structural optimization, and biological evaluations. (26th August 2020)

• Record Type: Journal Article
• Authors: Hu, Xueping; Ma, Xiaojuan; Cui, Jialin; Liu, Haishan; Zhu, Bin; Xie, Jin; Liang, Pei; Zhang, Li
• Is Part Of: Chemical biology & drug design. Volume 97:Number 1(2021)
• Page Start: 184
• Page End: 195
• Publication Date: 2020-08-26
• Subjects: ecdysone agonists -- ecdysone receptor -- fragment -- structure–activity relationship -- virtual screening; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13772
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract: 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. Abstract : A series of novel ecdysone receptor ligands 1‐phenyl‐4‐cyano‐5‐aminopyrazoles were discovered through combining structured‐based virtual screening, structural optimization, and biological evaluations. A further structural optimization of VS14 was provided as the basis for designing new ligands with improved activity. The most potent ligand I10 (IC50 = 0.64 μμ ) showed higher binding activity against Plutella xylostella ecdysone receptor than tebufenozide (RH‐5992, IC50 = 0.85 μμ ).