Abstract：
1,4-dihydropyridine derivatives (1,4-DHPs) are a class of drugs used to treat cardiovascular diseases, but these drugs can cause liver injury. To reveal the toxicity characteristics of these compounds, we used a series of assays, including cell viability, enzyme activity detection, and western blotting, to investigate the toxicity of seven kinds of 1,4-DHPs (0-100 μM) on HepG2 cells and establish 3D-QSAR model based on relevant toxicity data. After HepG2 cells were treated with 1,4-DHPs for 24 h, high-dose (100 μM) 1,4-DHPs decreased cell viability to varying degrees, while ROS and MDA contents were significantly increased, and ATP content was reduced. Moreover, with the concentration of 100 μM 1,4-DHPs (Nimodipine, Nitrendipine, Cilnidipine, and Manidipine) were markedly inhibited the phosphorylation levels of mTOR protein. The results of the 3D-QSAR model showed that the non-cross validation coefficient (R2) and cross validation coefficient (Q2) of the model were 0.982 and 0.652, respectively. Combined with external validation and the Williams diagram, the model showed good predictability and application domain. Based on the CoMSIA 3D contour map, the introduction of large volume and hydrogen bond receptor groups on the carbonyl oxygen side chains of the 1,4-DHPs ring 3- and 5- was beneficial for reducing the toxicity of 1,4-DHPs. The results of this study could supplement information on the cytotoxicity of 1,4-DHPs, and could provide theoretical support for predicting the toxicity of 1,4-DHPs.
摘要：
1,4-二氢吡啶衍生物（1,4-DHP）是一类用于治疗心血管疾病的药物，但是这些药物会导致肝损伤。为了揭示这些化合物的毒性特征，我们使用了一系列的检测方法,包括细胞活力，酶活性检测，和西方印迹，研究7种(0～100μM)1,4-DHP对HepG2细胞的毒性,并根据相关毒性数据建立3D-QSAR模型。HepG2细胞用1,4-DHP处理24小时后，高剂量（100μM）1,4-DHPs不同程度地降低细胞活力，而ROS和MDA含量显著增加,ATP含量降低。此外，浓度为100μM1,4-DHP(尼莫地平，尼群地平,西尼地平,和Manidipine）显着抑制mTOR蛋白的磷酸化水平。3D-QSAR模型的结果表明,模型的非交叉验证系数(R2)和交叉验证系数(Q2)分别为0.982和0.652。结合外部验证和威廉姆斯图，该模型具有良好的可预测性和应用领域。基于CoMSIA三维轮廓图,在1,4-DHPs环3-和5-的羰基氧侧链上引入大体积和氢键受体基团有利于降低1,4-DHPs的毒性。这项研究的结果可以补充有关1,4-DHPs的细胞毒性的信息，为预测1,4-DHP的毒性提供理论支持。
