背景:α-葡萄糖苷酶抑制剂能有效降低餐后血糖水平,控制糖尿病并发症的发生。五倍子单宁(GTs)由于其在体外具有显著的α-葡萄糖苷酶抑制活性而备受关注。然而,仍缺乏系统的比较研究来进一步阐明这些化合物对α-葡萄糖苷酶的体内和体外抑制活性,尤其是哺乳动物蔗糖酶和麦芽糖酶,并分析了它们的结构-活动关系。
目的:测定5种具有不同数量的没食子酰部分(GMs)的GTs对蔗糖酶的体外和体内抑制活性,麦芽糖酶和α-淀粉酶,并阐明了α-葡萄糖苷酶抑制活性与GMs的数量和连接方式之间的关系。
方法:采用分子对接和动力学研究了五种GTs对蔗糖酶的结合方式和结合能力,麦芽糖酶和α-淀粉酶。然后,这些化合物对蔗糖酶的抑制活性和抑制机制,使用抑制试验和酶抑制动力学研究了体外麦芽糖酶和α-淀粉酶。Further,通过对糖尿病模型小鼠的三个多糖耐受实验证明了这些化合物在体内的降血糖作用。
结果:分子对接的结果表明,这些化合物可以通过氢键与酶结合,疏水相互作用,等。此外,体外和体内的α-葡萄糖苷酶抑制比较研究表明,这些化合物对所有三种蔗糖酶的抑制活性,麦芽糖酶和α-淀粉酶排序为TA≈PGG>TeGG>TGG>1GG,它们的抑制活性随着GM数量的增加而增加。此外,1,2,3,4,6-五酰葡萄糖(PGG)和单宁酸(TA)在体外和体内的降血糖作用也被证实与阿卡波糖相当甚至更强。
结论:体外和体内GTs的α-葡萄糖苷酶抑制活性与GTs的数量呈正相关。数字越多,活动越强。然而,含5个GTs的PGG和含10个GTs的TA显示出几乎相同的α-葡萄糖苷酶抑制活性,可能是由于空间障碍导致的与酶的结合力降低。
BACKGROUND: α-Glucosidase inhibitors could effectively reduce postprandial blood glucose (PBG) levels and control the occurrence of complications of diabetes. Gallotannins (GTs) in plants have attracted much attention due to their significant α-glucosidase inhibitory activities in vitro. However, there is still a lack of systematic comparative studies to further elucidate inhibitory activities in vivo and in vitro of these compounds against α-glucosidase, especially for mammalian
sucrase and maltase, and analyze their structure-activity relationship.
OBJECTIVE: Determine the in vitro and in vivo inhibitory activities of five GTs with different number of galloyl moieties (GMs) on
sucrase, maltase and α-amylase, and elucidate the relationship between α-glucosidase inhibitory activities and the number and connection mode of GMs.
METHODS: Molecular docking and dynamics were used to study the binding mode and binding ability of five GTs against
sucrase, maltase and α-amylase. Then, the inhibitory activities and inhibitory mechanisms of these compounds on
sucrase, maltase and α-amylase in vitro were studied using inhibitory assay and enzyme inhibition kinetics. Further, the hypoglycemic effects in vivo of these compounds were demonstrated by three polysaccharides tolerance experiments on diabetes model mice.
RESULTS: The results of molecular docking showed that these compounds could bind to enzymes through hydrogen bonds, hydrophobic interactions, etc. In addition, the α-glucosidase inhibition comparative studies in vitro and in vivo demonstrated that the inhibitory activities of these compounds on all three
sucrase, maltase and α-amylase were ranked as TA ≈ PGG > TeGG > TGG > 1GG, and their inhibitory activities increases with the increase in the number of GMs. Moreover, the hypoglycemic effects of 1,2,3,4,6-pentagalloylglucose (PGG) and tannic acid (TA) in vitro and in vivo were also confirmed to be equivalent to or even stronger than that of acarbose.
CONCLUSIONS: α-Glucosidase inhibitory activities in vitro and in vivo of GTs were positively correlated with the number of GTs, and the more the number, the stronger the activity. However, PGG with five GTs and TA with ten GTs showed almost identical α-glucosidase inhibitory activities, possibly due to the reduced binding force with the enzyme caused by spatial hindrance.