Zadorozhnii Pavlo V, Kiselev Vadym V, Kharchenko Aleksandr V
Department of pharmacy and technology of organic substances, Ukrainian State University of Chemical Technology, Gagarin Ave., 8, Dnipro 49005, Ukraine.
Department of pharmacy and technology of organic substances, Ukrainian State University of Chemical Technology, Gagarin Ave., 8, Dnipro 49005, Ukraine.
Eur J Pharm Sci. 2020 Dec 1;155:105538. doi: 10.1016/j.ejps.2020.105538. Epub 2020 Sep 1.
This paper reports on a comprehensive in silico toxicity assessment of Salubrinal and its analogues containing a cinnamic acid residue or quinoline ring using the online servers admetSAR, ADMETlab, ProTox, ADVERPred, Pred-hERG and Vienna LiverTox. Apart from rare exceptions, in all 55 studied structures, mild or practical absence of acute toxicity was predicted for rats (III or IV toxicity class). Cardiotoxic, hepatotoxic and immunotoxic effects were predicted for Salubrinal and its analogues. We constructed models of the main predicted anti-targets hERG, BSEP, MRP3, MRP4 and AhR using the principle of homologous modeling. Molecular docking studies were carried out with the obtained models. We carried out molecular docking for all targets using AutoDock Vina, implemented in the PyRx 0.8 software package. According to the results of molecular docking, the compounds analyzed are potential moderate or weak hERG blockers. Induction of cholestasis and, as a consequence, liver damage by these drugs, directly related to inhibition of BSEP, MRP3 and MRP4, most likely will not be observed. Interaction with AhR for the studied compounds is impossible for steric reasons and, as a consequence, toxic effects on the immune and other organ systems associated with the activation of the AhR signaling pathway are excluded.
本文报道了使用在线服务器admetSAR、ADMETlab、ProTox、ADVERPred、Pred-hERG和Vienna LiverTox对Salubrinal及其含有肉桂酸残基或喹啉环的类似物进行的全面计算机毒性评估。除了极少数例外情况，在所有55个研究结构中，预测大鼠的急性毒性为轻度或实际上不存在（III或IV毒性等级）。预测Salubrinal及其类似物具有心脏毒性、肝毒性和免疫毒性作用。我们使用同源建模原理构建了主要预测抗靶点hERG、BSEP、MRP3、MRP4和AhR的模型。对获得的模型进行了分子对接研究。我们使用PyRx 0.8软件包中实现的AutoDock Vina对所有靶点进行了分子对接。根据分子对接结果，分析的化合物是潜在的中度或弱hERG阻滞剂。这些药物导致胆汁淤积进而引起肝损伤，这与BSEP、MRP3和MRP4的抑制直接相关，很可能不会被观察到。由于空间位阻原因，所研究的化合物与AhR不可能发生相互作用，因此排除了与AhR信号通路激活相关的对免疫和其他器官系统的毒性作用。
