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

Jin-ping Pang1, Xue-ping Hu1, Yun-xia Wang1, Jia-ning Liao1, Xin Chai1, Xu-wen Wang1, Chao Shen1, Jia-jia Wang2, Lu-lu Zhang2, Xin-yue Wang1, Feng Zhu1, Qin-jie Weng2, Lei Xu3, Ting-jun Hou1,4, Dan Li1
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
Correspondence to: Dan Li:,
DOI: 10.1038/s41401-021-00855-6
Received: 16 November 2021
Accepted: 27 December 2021
Advance online: 2 February 2022


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.
Keywords: 10.1038/s41401-021-00855-6

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