4.8 Article

Discovery of Novel GR Ligands toward Druggable GR Antagonist Conformations Identified by MD Simulations and Markov State Model Analysis

期刊

ADVANCED SCIENCE
卷 9, 期 3, 页码 -

出版社

WILEY
DOI: 10.1002/advs.202102435

关键词

glucocorticoid; ligand binding domain; Markov state model; nuclear receptor; virtual screening

资金

  1. National Natural Science Foundation of China [21575128, 81773632, 21907084]
  2. Natural Science Foundation of China of Zhejiang Province [LZ19H300001]
  3. Fundamental Research Funds for the Central Universities [2020QNA7003]
  4. Double Top-Class University Project [181201*194232101]

向作者/读者索取更多资源

Different ligands binding to the glucocorticoid receptor (GR) can induce varying conformational changes and biological functions. This study explored the folding pathway of helix 12 (H12) induced by different ligands through molecular dynamics simulations and discovered a novel GR ligand, HP-19, with promising anti-inflammatory activity in the nuclear factor-kappa B signaling pathway and no adverse effects on GR transactivation functions.
Binding of different ligands to glucocorticoid receptor (GR) may induce different conformational changes and even trigger completely opposite biological functions. To understand the allosteric communication within the GR ligand binding domain, the folding pathway of helix 12 (H12) induced by the binding of the agonist dexamethasone (DEX), antagonist RU486, and modulator AZD9567 are explored by molecular dynamics simulations and Markov state model analysis. The ligands can regulate the volume of the activation function-2 through the residues Phe737 and Gln738. Without ligand or with agonist binding, H12 swings from inward to outward to visit different folding positions. However, the binding of RU486 or AZD9567 perturbs the structural state, and the passive antagonist state appears more stable. Structure-based virtual screening and in vitro bioassays are used to discover novel GR ligands that bias the conformation equilibria toward the passive antagonist state. HP-19 exhibits the best anti-inflammatory activity (IC50 = 0.041 +/- 0.011 mu m) in nuclear factor-kappa B signaling pathway, which is comparable to that of DEX. HP-19 also does not induce adverse effect-related transactivation functions of GR. The novel ligands discovered here may serve as promising starting points for the development of GR modulators.

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