2. Academic Validation
  3. Discovery of Novel GR Ligands toward Druggable GR Antagonist Conformations Identified by MD Simulations and Markov State Model Analysis

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

  • Adv Sci (Weinh). 2022 Jan;9(3):e2102435. doi: 10.1002/advs.202102435.
Xueping Hu 1 2,  Jinping Pang 1,  Jintu Zhang 1,  Chao Shen 1,  Xin Chai 1,  Ercheng Wang 1,  Haiyi Chen 1,  Xuwen Wang 1,  Mojie Duan 3,  Weitao Fu 1,  Lei Xu 4,  Yu Kang 1,  Dan Li 1,  Hongguang Xia 5,  Tingjun Hou 1 2
Affiliations

Affiliations

  • 1 Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 2 State Key Lab of CAD&CG, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 3 Key Laboratory of magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, Hubei, 430071, China.
  • 4 Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, 213001, China.
  • 5 Department of Biochemistry and Research Center of Clinical Pharmacy of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
PMID: 34825505 DOI: 10.1002/advs.202102435
Abstract

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 µm) 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.

Keywords

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

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