Development of 3D-QSAR models for predicting the activities of chemicals to stimulate muscle growth via β-adrenoceptor.

β-adrenoceptor (βAR) agonists can stimulate skeletal muscle growth. Their illegal use in food-producing animals, human athletes and bodybuilders causes adverse health effects. In the present study, we developed 3D-QSAR models for predicting the activity of chemicals which can stimulate skeletal muscle growth through βAR. The activity of 25 βAR agonists was measured by βAR-cAMP response element (CRE) -luciferase (Luc) reporter assay. The 3D-QSAR models were built using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The CoMFA and CoMSIA models displayed high external predictability (R 0.996 and 0.992, respectively) and good statistical robustness, and revealed that electrostatic effects were the most prominent forces influencing the activity of βAR agonists. The CoMFA and CoMSIA contour plots provided clues regarding the main chemical features responsible for the activity variations and also resulted in predictions which correlate very well with the observed activity. In vitro study with differentiated myotubes showed that the potency orders of βAR agonists in activating the βAR-CRE-Luc reporter and in upregulating CREB target genes related to muscle growth were consistent. These 3D-QSAR models provide tools for predicting the activity of chemicals which might be illegally used in livestock or humans to stimulate skeletal muscle growth.