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

  • Acta Pharmacol Sin. 2022 Sep;43(9):2429-2438. doi: 10.1038/s41401-021-00855-6.
Jin-Ping Pang   #  1 ,  Xue-Ping Hu   #  1 ,  Yun-Xia Wang  1 ,  Jia-Ning Liao  1 ,  Xin Chai  1 ,  Xu-Wen Wang  1 ,  Chao Shen  1 ,  Jia-Jia Wang  2 ,  Lu-Lu Zhang  2 ,  Xin-Yue Wang  1 ,  Feng Zhu  1 ,  Qin-Jie Weng  2 ,  Lei Xu  3 ,  Ting-Jun Hou  1  4 ,  Dan Li  5
Affiliations
  • 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.
  • 5. Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. [email protected].
  • # Contributed equally.
PMID: 35110698 DOI: 10.1038/s41401-021-00855-6
Abstract

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
SGRMs; anti-inflammation; glucocorticoid receptor; transrepression.
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