Department of Toxicology and Bromatology, Faculty of Pharmacy, L. Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, A. Jurasza 2 Street, PL-85089 Bydgoszcz, Poland.
Department of Medical Biology and Biochemistry, Faculty of Medicine, L. Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Karłowicza 24 Street, PL-85092 Bydgoszcz, Poland.
Nutrients. 2022 Aug 26;14(17):3521. doi: 10.3390/nu14173521.
Stevioside, one of the natural sweeteners extracted from stevia leaves, and its derivatives are considered to have numerous beneficial pharmacological properties, including the inhibition of activated coagulation factor X (FXa). FXa-PAR signaling is a possible therapeutic target to enhance impaired metabolism and insulin resistance in obesity. Thus, the goal of the investigation was a QSAR analysis using multivariate adaptive regression splines (MARSplines) applied to a data set of 20 isosteviol derivatives bearing thiourea fragments with possible FXa inhibitory action. The best MARS submodel described a strong correlation between FXa inhibitory activity and molecular descriptors, such as: B01[C-Cl], E2m, L3v, Mor06i, RDF070i and HATS7s. Five out of six descriptors included in the model are geometrical descriptors quantifying three-dimensional aspects of molecular structure, which indicates that the molecular three-dimensional conformation is of high significance for the MARSplines modeling procedure and obviously for FXa inhibitory activity. High model performance was confirmed through an extensive validation protocol. The results of the study not only confirmed the enhancement in pharmacological activity by the presence of chlorine in a phenyl ring, but also, and primarily, may provide the basis for searching for new active isosteviol analogues, which may serve as drugs or health-beneficial food additives in patients suffering from obesity and comorbidities.
甜菊苷是从甜叶菊叶子中提取的天然甜味剂之一，其衍生物被认为具有许多有益的药理特性，包括抑制激活的凝血因子 X (FXa)。FXa-PAR 信号转导可能是治疗肥胖症中代谢受损和胰岛素抵抗的靶点。因此，研究的目的是使用多元自适应回归样条 (MARSplines) 对 20 种具有潜在 FXa 抑制作用的异甜菊醇衍生物的数据集进行 QSAR 分析。最佳 MARS 子模型描述了 FXa 抑制活性与分子描述符之间的强烈相关性，例如：B01[C-Cl]、E2m、L3v、Mor06i、RDF070i 和 HATS7s。模型中包含的六个描述符中有五个是几何描述符，它们定量了分子结构的三维方面，这表明分子的三维构象对于 MARSplines 建模过程具有重要意义，显然对于 FXa 抑制活性也具有重要意义。通过广泛的验证协议确认了模型的高性能。该研究的结果不仅证实了苯环中氯的存在会增强药理活性，而且还可能为寻找新的具有活性的异甜菊醇类似物提供基础，这些类似物可能作为肥胖症和合并症患者的药物或有益于健康的食品添加剂。
