Discovery of a novel nonsteroidal selective glucocorticoid receptor modulator by virtual screening and bioassays  

作　　者：Jin-ping Pang Xue-ping Hu Yun-xia Wang Jia-ning Liao Xin Chai Xu-wen Wang Chao Shen Jia-jia Wang Lu-lu Zhang Xin-yue Wang Feng Zhu Qin-jie Weng Lei Xu Ting-jun Hou Dan Li 

机构地区：[1]Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,China [2]State Key Lab of CAD&CG,Zhejiang University,Hangzhou 310058,China [3]Institute of Bioinformatics and Medical Engineering,School of Electrical and Information Engineering,Jiangsu University of Technology,Changzhou 213001,China [4]Center for Drug Safety Evaluation and Research,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,China

出　　处：《Acta Pharmacologica Sinica》2022年第9期2429-2438,共10页中国药理学报（英文版）

基　　金：This study was supported by the Key R&D Program of Zhejiang Province(2020C03010);National Natural Science Foundation of China(81773632,21907084);Zhejiang Provincial Natural Science Foundation of China(LZ19H300001);the Key R&D Program of Zhejiang Province(2019C02024).

摘　　要：Synthetic glucocorticoids(GCs)have been widely used in the treatment of a broad range of inflammatory diseases,but their clinic use is limited by undesired side effects such as metabolic disorders,osteoporosis,skin and muscle atrophies,mood disorders and hypothalamic-pituitary-adrenal(HPA)axis suppression.Selective glucocorticoid receptor modulators(SGRMs)are expected to have promising anti-inflammatory efficacy but with fewer side effects caused by GCs.Here,we reported HT-15,a prospective SGRM discovered by structure-based virtual screening(VS)and bioassays.HT-15 can selectively act on the NF-κB/AP1-mediated transrepression function of glucocorticoid receptor(GR)and repress the expression of pro-inflammation cytokines(i.e.,IL-1β,IL-6,COX-2,and CCL-2)as effectively as dexamethasone(Dex).Compared with Dex,HT-15 shows less transactivation potency that is associated with the main adverse effects of synthetic GCs,and no cross activities with other nuclear receptors.Furthermore,HT-15 exhibits very weak inhibition on the ratio of OPG/RANKL.Therefore,it may reduce the side effects induced by normal GCs.The bioactive compound HT-15 can serve as a starting point for the development of novel therapeutics for high dose or long-term anti-inflammatory treatment.

关 键 词：glucocorticoid receptor ANTI-INFLAMMATION SGRMs transrepression 

分 类 号：R965[医药卫生—药理学]