CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Toxicol In Vitro. 2021 Dec;77:105251. doi: 10.1016/j.tiv.2021.105251. Epub 2021 Sep 30.
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.
β-肾上腺素受体 (βAR) 激动剂可刺激骨骼肌生长。它们在食用动物、人类运动员和健美运动员中的非法使用会对健康产生不利影响。在本研究中，我们开发了 3D-QSAR 模型，用于预测可通过 βAR 刺激骨骼肌生长的化学物质的活性。通过 βAR-cAMP 反应元件 (CRE)-荧光素酶 (Luc) 报告基因测定来测量 25 种 βAR 激动剂的活性。使用比较分子场分析 (CoMFA) 和比较分子相似性指数分析 (CoMSIA) 构建了 3D-QSAR 模型。CoMFA 和 CoMSIA 模型显示出较高的外部预测能力（分别为 0.996 和 0.992）和良好的统计稳健性，并表明静电效应是影响 βAR 激动剂活性的最主要因素。CoMFA 和 CoMSIA 轮廓图提供了有关主要化学特征的线索，这些特征负责活性变化，并导致与观察到的活性非常相关的预测。在分化肌管的体外研究中，βAR 激动剂激活 βAR-CRE-Luc 报告基因和上调与肌肉生长相关的 CREB 靶基因的效力顺序一致。这些 3D-QSAR 模型为预测可能在牲畜或人类中非法用于刺激骨骼肌生长的化学物质的活性提供了工具。
