Discovery of novel non-steroidal selective glucocorticoid receptor modulators by structure- and IGN-based virtual screening, structural optimization, and biological evaluation

Xueping Hu; Jinping Pang; Changwei Chen; Dejun Jiang; Chao Shen; Xin Chai; Liu Yang; Xujun Zhang; Lei Xu; Sunliang Cui; Tingjun Hou; Dan Li

doi:10.1016/j.ejmech.2022.114382

Discovery of novel non-steroidal selective glucocorticoid receptor modulators by structure- and IGN-based virtual screening, structural optimization, and biological evaluation

Eur J Med Chem. 2022 Jul 5:237:114382. doi: 10.1016/j.ejmech.2022.114382. Epub 2022 Apr 20.

Authors

Xueping Hu¹, Jinping Pang², Changwei Chen³, Dejun Jiang², Chao Shen², Xin Chai², Liu Yang², Xujun Zhang², Lei Xu⁴, Sunliang Cui³, Tingjun Hou¹, Dan Li⁵

Affiliations

¹ Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China; State Key Lab of CAD&CG, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
² Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
³ Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
⁴ Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, 213001, China.
⁵ Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China. Electronic address: lidancps@zju.edu.cn.

PMID: 35483323
DOI: 10.1016/j.ejmech.2022.114382

Abstract

Glucocorticoids (GCs) are the most commonly used anti-inflammatory drugs. However, their excellent therapeutic effects are often accompanied by undesirable side effects. To discover selective glucocorticoid receptor modulators (SGRMs) that preferentially induce transrepression with little or no transactivation activity, a structure-based virtual screening by combining molecular docking and InteractionGraphNet (IGN) rescoring was performed, and compound HP210 was identified. HP210 did not induce the transactivation functions of GR while still acted on the NF-κB mediated tethered transrepression function (IC₅₀ = 2.32 μM), and suppressed the secretion of pro-inflammation cytokines IL-1β and IL-6. Compared with dexamethasone, HP210 showed no cross activities with phylogenetically related mineralcorticoid receptor and progesterone receptor and no significant effect on osteoprotegerin, exhibiting a reduced side-effect profile. Then, guided by the molecular dynamics simulations and binding free energy calculations, compound HP210_b4 with over two-fold higher transrepression activity (IC₅₀ = 0.99 μM) was discovered. This study reported a group of non-steroidal new-scaffold SGRMs, providing valuable clues for the development of novel anti-inflammatory drugs.

Keywords: Glucocorticoid receptor; InteractionGraphNet; Molecular dynamics simulation; Selective glucocorticoid receptor modulators; Virtual screening.

MeSH terms

Anti-Inflammatory Agents / pharmacology
Glucocorticoids* / pharmacology
Molecular Docking Simulation
NF-kappa B / metabolism
Receptors, Glucocorticoid* / chemistry

Substances

Anti-Inflammatory Agents
Glucocorticoids
NF-kappa B
Receptors, Glucocorticoid