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.
复制标题
通过 MD 模拟和马尔可夫态模型分析发现新型 GR 配体，用于药物化 GR 拮抗剂构象
DOI：
10.1002/advs.202102435
复制
发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Hou T
中科院分区：
文献类型：
--
作者：
Hu X;Pang J;Zhang J;Shen C;Chai X;Wang E;Chen H;Wang X;Duan M;Fu W;Xu L;Kang Y;Li D;Xia H;Hou T
不同配体与糖皮质激素受体（GR）的结合可能引起不同的构象变化，甚至引发完全相反的生物学功能。为了了解 GR 配体结合域内的变构通讯，通过分子动力学模拟和马尔可夫状态模型分析探索了激动剂地塞米松 (DEX)、拮抗剂 RU486 和调节剂 AZD9567 结合诱导的螺旋 12 (H12) 折叠途径。配体可以通过残基 Phe737 和 Gln738 调节激活函数-2 的体积。在没有配体或激动剂结合的情况下，H12 从内到外摆动以访问不同的折叠位置。然而，RU486 或 AZD9567 的结合扰乱了结构状态，被动拮抗状态显得更稳定。基于结构的虚拟筛选和体外生物测定用于发现新型 GR 配体，使构象平衡偏向被动拮抗状态。 HP-19 在核因子-κ B 信号通路中表现出最佳的抗炎活性（IC50 = 0.041 ± 0.011 µm），与 DEX 相当。 HP-19 也不会诱导与不良反应相关的 GR 反式激活功能。这里发现的新型配体可能作为 GR 调节剂开发的有希望的起点。
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.
登录
查看更多内容
影响因子：
5.5
作者：
Goetz, Andreas W.;Williamson, Mark J.;Xu, Dong;Poole, Duncan;Le Grand, Scott;Walker, Ross C.
通讯作者：
Walker, Ross C.
影响因子：
4.1
作者：
LAMBRAKOS, SG;BORIS, JP;NAGUMO, M
通讯作者：
NAGUMO, M
影响因子：
64.5
作者：
Bledsoe, RK;Montana, VG;Xu, HE
通讯作者：
Xu, HE
影响因子：
1.6
作者：
Metzner, Philipp;Schuette, Christof;Vanden-Eijnden, Eric
通讯作者：
Vanden-Eijnden, Eric
影响因子：
4.8
作者：
Hu, Xiao;Du, Sarah;Obukowicz, Mark G.
通讯作者：
Obukowicz, Mark G.