Chemical systems biology reveals mechanisms of glucocorticoid receptor signaling.

Glucocorticoids display remarkable anti-inflammatory activity, but their use is limited by on-target adverse effects including insulin resistance and skeletal muscle atrophy. We used a chemical systems biology approach, Ligand Class Analysis (LCA), to examine ligands designed to modulate glucocorticoid receptor activity through distinct structural mechanisms. These ligands displayed diverse activity profiles, providing the variance required to identify target genes and coregulator interactions that were highly predictive of their effects on myocyte glucose disposal and protein balance. Their anti-inflammatory effects were linked to glucose disposal but not muscle atrophy. This approach also predicted selective modulation in vivo, identifying compounds that were muscle sparing or anabolic for protein balance and mitochondrial potential. LCA defined the mechanistic links between the ligand-receptor interface and ligand-driven physiological outcomes, a general approach that can be applied to any ligand-regulated allosteric signaling system.

糖皮质激素具有显著的抗炎活性，但其使用受到靶向不良反应的限制，包括胰岛素抵抗和骨骼肌萎缩。我们采用一种化学系统生物学方法——配体类别分析（LCA），来研究旨在通过不同结构机制调节糖皮质激素受体活性的配体。这些配体表现出不同的活性特征，提供了识别靶基因和辅调节因子相互作用所需的差异，而这些对于预测它们对肌细胞葡萄糖处置和蛋白质平衡的影响具有高度预测性。它们的抗炎作用与葡萄糖处置有关，但与肌肉萎缩无关。这种方法还预测了体内的选择性调节，确定了对蛋白质平衡和线粒体电位具有肌肉保护或合成代谢作用的化合物。LCA明确了配体 - 受体界面和配体驱动的生理结果之间的机制联系，这是一种可应用于任何配体调节的变构信号系统的通用方法。