TY - JOUR T1 - Chemical Systems Biology Reveals Mechanisms of Dissociated Glucocorticoid Receptor Signaling JF - bioRxiv DO - 10.1101/2020.06.15.153270 SP - 2020.06.15.153270 AU - Nelson E. Bruno AU - Jerome C. Nwachukwu AU - Sathish Srinivasan AU - Charles C. Nettles AU - Tina Izard AU - Zhuang Jin AU - Siddaraju V. Boregowda AU - Donald G. Phinney AU - Olivier Elemento AU - Xu Liu AU - Eric A. Ortlund AU - René Houtman AU - Diana A. Stavreva AU - Gordon L. Hager AU - Theodore M. Kamenecka AU - Douglas J. Kojetin AU - Kendall W. Nettles Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/06/16/2020.06.15.153270.abstract N2 - 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 dissociated activity in vivo, identifying compounds that were muscle sparing or anabolic for protein balance and mitochondrial potential. LCA defines the mechanistic links between the ligand-receptor interface and the ligand-driven physiological outcomes, a general approach that can be applied to any ligand-regulated allosteric signaling system.Competing Interest StatementThe authors have declared no competing interest. ER -