Computer-aided discovery of novel aryl hydrocarbon receptor ligands to regulate CYP1A1 expression in inflammatory macrophages
作者全名：Chen, Kerui; Luo, Li; Tu, Gao; Yang, Jingyi; Pu, Wang; Zhu, Junyu; Xue, Weiwei; Zhang, Rui
作者地址：[Chen, Kerui; Pu, Wang; Zhang, Rui] Chongqing Med Univ, Affiliated Hosp 1, Dept Resp & Crit Care Med, 1 Youyi Rd, Chongqing 400016, Peoples R China; [Luo, Li; Zhu, Junyu] Army Med Univ, Army Med Ctr, Res Dept 1, Chongqing, Peoples R China; [Tu, Gao; Yang, Jingyi; Xue, Weiwei] Chongqing Univ, Sch Pharmaceut Sci, Chongqing 401331, Peoples R China
通信作者：Zhang, R (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Resp & Crit Care Med, 1 Youyi Rd, Chongqing 400016, Peoples R China.; Xue, WW (通讯作者)，Chongqing Univ, Sch Pharmaceut Sci, Chongqing 401331, Peoples R China.
来源：CHEMICAL BIOLOGY & DRUG DESIGN
ESI学科分类：BIOLOGY & BIOCHEMISTRY
WOS号：WOS:001258207700001
JCR分区：Q2
影响因子：3.2
年份：2024
卷号：103
期号：6
开始页：
结束页：
文献类型：Article
关键词：anti-inflammation; aryl hydrocarbon receptor; CYP1A1; ensemble docking; ligand
摘要：The environmental factor aryl hydrocarbon receptor (AhR), a key protein connecting the external environmental signals (e.g., environmental endocrine disruptor TCDD) to internal cellular processes, is involved in the activation of peripheral macrophages and inflammatory response in human body. Thus, there is widespread interest in finding compounds to anti-inflammatory response in macrophages by targeting human AhR. Here, ensemble docking based-virtual screening was first used to screen a library (similar to 200,000 compounds) against human AhR ligand binding domain (LBD) and 25 compounds were identified as potential inhibitors. Then, 9 out of the 25 ligands were found to down-regulate the mRNA expression of CYP1A1 (a downstream gene of AhR signaling) in AhR overexpressing macrophages. The most potent compound AE-411/41415610 was selected for further study and found to reduce both mRNA and protein expressions level of CYP1A1 in mouse peritoneal macrophage. Moreover, protein chip signal pathway analysis indicated that AE-411/41415610 play a role in regulating JAK-STAT and AKT-mTOR pathways. In sum, the discovered hits with novel scaffolds provided a starting point for future design of more effective AhR-targeted lead compounds to regulate CYP1A1 expression of inflammatory peritoneal macrophages.
基金机构：Natural Science Foundation of Chongqing [2023NSCQ- MSX0140]; Technology Innovation and Application Demonstration Project of Chongqing [cstc2018jscx- msybX0287]; Natural Science Foundation of Chongqing [2023NSCQ- MSX0140]
基金资助正文：the Natural Science Foundation of Chongqing, Grant/Award Number: 2023NSCQ- MSX0140; the Technology Innovation and Application Demonstration Project of Chongqing, Grant/Award Number: cstc2018jscx- msybX0287.This work was supported by the Natural Science Foundation of Chongqing (2023NSCQ- MSX0140), the Technology Innovation and Application Demonstration Project of Chongqing (cstc2018jscx- msybX0287)
