Identification of 1-phenyl-4-cyano-5-aminopyrazoles as novel ecdysone receptor ligands by virtual screening, structural optimization, and biological evaluations
Identification of 1-phenyl-4-cyano-5-aminopyrazoles as novel ecdysone receptor ligands by virtual screening, structural optimization, and biological evaluations
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通过虚拟筛选、结构优化和生物学评价鉴定 1-苯基-4-氰基-5-氨基吡唑作为新型蜕皮激素受体配体
DOI：
10.1111/cbdd.13772
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发表时间：
2020-08-26
影响因子：
3
通讯作者：
Zhang, Li
中科院分区：
文献类型：
--
作者：
Hu, Xueping;Ma, Xiaojuan;Zhang, Li
蜕皮激素通过与昆虫蜕皮激素受体（ecdysone receptor，EcR）结合而启动昆虫的蜕皮过程，是鉴定昆虫生长调节因子的一个很有前途的靶标。本文提出了一种用于鉴定新的EcR配体的计算机/体外筛选程序。三步虚拟筛选程序使用三维药效团模型、对接和分子力学/泊松-玻尔兹曼表面积（MM/PBSA）重新评分程序。从超过200，000种化学物质的文库中鉴定出对PlutellaxylostellaEcR具有良好结合活性的新命中物（VS 14）。随后，合成了1-苯基-4-氰基-5-氨基吡唑骨架和12个EcR配体。它们对小菜蛾EcR的IC（50）值范围为0.64 ~ 23.21 μ m。此外，对新型支架的构效关系进行了初步分析，为设计具有更高活性的新型配体提供了基础。
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 againstPlutellaxylostellaEcR 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 againstPlutella xylostellaEcR ranged from 0.64 to 23.21 mu m. Furthermore, a preliminary analysis of the structure-activity relationship for novel scaffolds provided a basis for designing new ligands with improved activity.