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

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.

Vertical profile, contamination assessment of mercury and arsenic in sediment cores from typical intertidal zones of China.

The vertical profiles, contamination levels, and potential ecological risks of mercury and arsenic were studied from the sediment cores of seven typical intertidal zones, including the Liaohe River Estuary, the Jianhe River Estuary, the Dagu River Estuary, Yancheng Shoal, the Dongtan Yangtze River Estuary, Hangzhou Bay, and the Pearl River Estuary. Marine sediment quality standards, the threshold effect level (TEL), and the probable effect level (PEL) were used as guidelines to evaluate sediment quality. In addition, the geo-accumulation index (Igeo) and potential ecological risk index ([Formula: see text]) were used to assess contamination and potential ecological risks from mercury and arsenic. The results showed that the Pearl River Estuary was moderately polluted by mercury and represented a high potential ecological risk, while other areas were uncontaminated or mildly contaminated with low or moderate potential ecological risks. The Pearl River Estuary was mildly polluted by arsenic and represented a mild potential ecological risk, while other areas were unpolluted and also posed a mild potential ecological risk.