用于抑制二肽基肽酶-IV的活性植物化学物质：计算机模拟和实验方法。
Active phytochemicals of for DPP-IV inhibition: in silico and experimental approach.
作者信息
Srivastava Shivani, Shree Priya, Tripathi Yamini Bhusan
机构信息
Department of Medicinal Chemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, U.P India.
出版信息
J Diabetes Metab Disord. 2017 Nov 21;16:46. doi: 10.1186/s40200-017-0328-0. eCollection 2017.
BACKGROUND
We had earlier reported that the extract of significantly inhibits DPP-IV enzyme, resulting in glucose tolerance response in rats. In this study, we have explored the active phytochemicals responsible for this potential. The results have been validated in both fasting and postprandial states in the plasma of normal rats and also in fasting blood and intestinal homogenates of diabetic models.
METHODS
water extract (PTWE) was administered to normal Charles Foster rats for 35 days and to diabetic model (65 mg/kg bw) for 10 days. After treatments, oral glucose tolerance test (OGTT) and insulin was done for 90 min, and the changes in the levels of GLP-1, GIP, and DPP-IV activities were monitored in fasting and postprandial states. In the case of the diabetic model, DPP-IV activity was measured in intestinal homogenate and basal insulin in plasma. The components of PTWE were analyzed via HPLC-MS based on their chemical formula, molecular mass, and retention time. Using the molecular docking study, we have selected the top five components having strong binding energy with DPP-IV.
RESULTS
The increase in secretion of GLP-1 and GIP was significantly higher in the postprandial state when compared to fasting condition. GLP-1 plasma concentration increased by 5.8 and 2.9 folds and GIP increased by 8.7 and 2.4 folds in PTWE and control rats, respectively. In contrast, the postprandial decrease in DPP-IV specific activities was recorded at 2.3 and 1.4 folds. The response in OGTT and insulin was also consistent with these changes. In comparison to diabetic controls, PTWE-administered rats showed decreased DPP-IV activity in the intestine, leading to enhanced basal insulin concentration. Through molecular docking, we found Puerarone and Robinin to be the most potential phytochemicals of PTWE for DPP-IV inhibition. Binding energy (kcal/mol) and dissociation constant (pM) of Robinin with DPP-IV protein were found to be 7.543 and 2,957,383.75, respectively. For Puerarone, it was 7.376 and 3,920,309, respectively.
CONCLUSIONS
Thus, this study provides the novel active components that contribute to the DPP-IV inhibitory property of PTWE.
背景
我们之前报道过，[提取物名称]的提取物能显著抑制二肽基肽酶-IV（DPP-IV）酶，从而使大鼠产生葡萄糖耐量反应。在本研究中，我们探究了造成这种潜力的活性植物化学物质。研究结果在正常大鼠血浆的空腹和餐后状态下以及糖尿病模型的空腹血液和肠道匀浆中均得到了验证。
方法
将水提取物（PTWE）给予正常的查尔斯·福斯特大鼠35天，给予糖尿病模型（65毫克/千克体重）10天。处理后，进行90分钟的口服葡萄糖耐量试验（OGTT）和胰岛素检测，并监测空腹和餐后状态下胰高血糖素样肽-1（GLP-1）、葡萄糖依赖性促胰岛素多肽（GIP）水平的变化以及DPP-IV活性。对于糖尿病模型，检测肠道匀浆中的DPP-IV活性和血浆中的基础胰岛素水平。基于PTWE的化学式、分子量和保留时间，通过高效液相色谱-质谱联用（HPLC-MS）分析其成分。利用分子对接研究，我们挑选出了与DPP-IV具有强结合能的前五种成分。
结果
与空腹状态相比，餐后状态下GLP-1和GIP的分泌增加显著更高。PTWE组大鼠和对照组大鼠的血浆GLP-1浓度分别增加了5.8倍和2.9倍，GIP分别增加了8.7倍和2.4倍。相比之下，餐后DPP-IV比活性的降低分别为2.3倍和1.4倍。OGTT和胰岛素的反应也与这些变化一致。与糖尿病对照组相比，给予PTWE的大鼠肠道中的DPP-IV活性降低，导致基础胰岛素浓度升高。通过分子对接，我们发现葛根素和刺槐素是PTWE中对DPP-IV抑制作用最具潜力的植物化学物质。刺槐素与DPP-IV蛋白的结合能（千卡/摩尔）和解离常数（皮摩尔）分别为7.543和2,957,383.75。葛根素的分别为7.376和3,920,309。
结论
因此，本研究提供了有助于PTWE的DPP-IV抑制特性的新型活性成分。
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