【摘要】 目的探索3-[4-（苯基磺酰胺）苯甲酰]-2H-1-苯并吡喃-2-酮母核结构化合物YG-18在小鼠体内的降糖作用,初步评价其安全性,利用分子对接技术验证YG-18对α-葡萄糖苷酶的抑制方式。方法将ICR小鼠随机分为对照组、阿卡波糖组与YG-18(7.23 mg·kg^-1)组,分别负荷蔗糖与葡萄糖,检测负荷后0、0.5、1、2 h时的血糖值,计算血糖浓度-时间曲线下面积（AUC）;根据OECD急性毒性实验指导原则,观察KM小鼠在给药后4 h、48 h和14 d内的毒性反应和存活状态,实验结束后解剖小鼠观察小鼠器官的形态、颜色、质地;利用分子对接将其与α-葡萄糖苷酶共结晶结构中的活性位点对接,预测其抑制α-葡萄糖苷酶的方式。结果 7.23 mg·kg^-1的YG-18降低了正常ICR小鼠蔗糖负荷后的血糖峰值（P<0.05）与2 h内血糖浓度-时间曲线下面积（P<0.001）;在OECD指导原则中极限浓度2000 mg·kg^-1剂量下,KM小鼠14 d内除腹泻外,未出现其他毒性反应并全部存活,器官的形态、颜色、质地未有明显变化。分子对接结果显示,YG-18可能会与酶结构中的GLN 279、ARG 315、GLU 411等氨基酸残基形成氢键;除氢键外,其可能还与ASP 69、ASP 215、GLU 277氨基酸残基形成范德华力相互作用。结论本研究证实了YG-18是一种在体内具有较好的降糖作用的、安全性高的新型α-葡萄糖苷酶抑制剂,与α-葡萄糖苷酶的预测结合作用主要为氢键、范德华力等相互作用力。更多还原

【Abstract】 Objective To determine the hypoglycemic effect and the safety of 3-[4-（phenylsulfonamide）benzoyl]-2 H-1-benzopyran-2-one core structure compound YG-18 in mice, and to verify the mechanism of its α-glucosidase inhibition with molecular docking simulation. Methods The ICR mice were randomly divided into a control group, an acarbose group and a YG-18(7.23 mg·kg^-1) group, receiving intragastric administration of sucrose and glucose respectively. The concentration of blood glucose was analyzed at 0, 0.5, 1, and 2 h after the intragastric administration. The area under the curve（AUC） was calculated. An acute oral toxicity study was performed according to OECD guidelines. The toxicity and survival of the KM mice were observed at 4 h, 48 h and 14 d after the intragastric administration. The mice were sacrificed and dissected for gross examination（including the organ morphology, color, and texture）. Molecular docking simulation was used to predict the interaction patterns between YG-18 and the active sites of the co-crystallized structure of α-glucosidase. Results YG-18(7.23 mg·kg^-1) lowered the peak value of blood glucose after the sucrose loading in normal ICR mice（P<0.05） and decreased the AUC of blood glucose within 2 h（P<0.001）. At the limit test dose of 2000 mg·kg^-1 based on OECD guidelines, all KM mice survived and no toxicities except diarrhea were observed within 14 d. There were no significant changes in the organs morphology, color and texture. Molecular docking showed that YG-18 might form hydrogen bonds with GLN 279, ARG 315, GLU 411 amino acid residues, and might form van der Waals interaction with ASP 69, ASP 215, and GLU 277 amino acid residues of α-glucosidase structure.Conclusion YG-18 is a novel α-glucosidase inhibitor with a good hypoglycemic effect and a safety profile. YG-18 may form hydrogen bonds and van der Waals interaction with α-glucosidase.更多还原