Center for Anesthesiology and Reanimatology, Clinical Center Niš, Niš, Serbia.
Clinic for Cardiosurgery, Clinical Center Niš, Niš, Serbia.
Comput Biol Chem. 2018 Aug;75:32-38. doi: 10.1016/j.compbiolchem.2018.04.009. Epub 2018 Apr 13.
Up to this date, there has been an ongoing debate about the mode of action of general anesthetics, which have postulated many biological sites as targets for their action. However, postoperative nausea and vomiting are common problems in which inhalational agents may have a role in their development. When a mode of action is unknown, QSAR modelling is essential in drug development. To investigate the aspects of their anesthetic, QSAR models based on the Monte Carlo method were developed for a set of polyhalogenated ethers. Until now, their anesthetic action has not been completely defined, although some hypotheses have been suggested. Therefore, a QSAR model should be developed on molecular fragments that contribute to anesthetic action. QSAR models were built on the basis of optimal molecular descriptors based on the SMILES notation and local graph invariants, whereas the Monte Carlo optimization method with three random splits into the training and test set was applied for model development. Different methods, including novel Index of ideality correlation, were applied for the determination of the robustness of the model and its predictive potential. The Monte Carlo optimization process was capable of being an efficient in silico tool for building up a robust model of good statistical quality. Molecular fragments which have both positive and negative influence on anesthetic action were determined. The presented study can be useful in the search for novel anesthetics.
迄今为止，关于全身麻醉剂的作用模式一直存在争议，许多生物靶点都被认为是其作用的目标。然而，术后恶心和呕吐是常见的问题，吸入性麻醉剂可能在其发生发展中起作用。当作用模式未知时，定量构效关系（QSAR）建模在药物开发中至关重要。为了研究其麻醉作用的各个方面，我们基于蒙特卡罗方法为一组多卤代醚开发了 QSAR 模型。到目前为止，虽然已经提出了一些假设，但它们的麻醉作用尚未完全定义。因此，应该针对有助于麻醉作用的分子片段开发 QSAR 模型。QSAR 模型是基于基于 SMILES 符号和局部图不变量的最佳分子描述符构建的，而蒙特卡罗优化方法则应用于三个随机拆分到训练集和测试集的方法来开发模型。为了确定模型的稳健性及其预测潜力，应用了不同的方法，包括新颖的理想相关指数。蒙特卡罗优化过程能够成为构建具有良好统计质量的稳健模型的有效计算工具。确定了对麻醉作用具有正反两方面影响的分子片段。本研究有助于寻找新型麻醉剂。
