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, 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. Ligand class analysis 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.

糖皮质激素显示出显着的抗炎活性，但它们的使用受到包括胰岛素抵抗和骨骼肌萎缩在内的靶向不良反应的限制。我们使用化学系统生物学方法、配体类别分析来检查旨在通过不同结构机制调节糖皮质激素受体活性的配体。这些配体显示出不同的活性特征，提供了识别目标基因和共调节相互作用所需的差异，这些相互作用高度预测了它们对肌细胞葡萄糖处理和蛋白质平衡的影响。它们的抗炎作用与葡萄糖处理有关，但与肌肉萎缩无关。这种方法还预测了体内的选择性调节，识别出保护肌肉或促进蛋白质平衡和线粒体潜能的化合物。