针对α-葡萄糖苷酶的潜在抗糖尿病药物羟基黄酮衍生物的计算机设计、合成和评价

Q4 Pharmacology, Toxicology and Pharmaceutics
Riya Saikia, Aparoop Das, K. Pathak, Neelutpal Gogoi, Tirna Paul, J. Sahariah, H. Sarma
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引用次数: 0

摘要

葡糖苷酶是一种催化酶,在碳水化合物代谢的最后一步催化,特别是水解,使血液中的碳水化合物释放葡萄糖单位。到目前为止,许多具有α-葡萄糖苷酶抑制活性的化合物,如阿卡波糖、伏格列糖等,已被用于糖尿病治疗并商业化。然而,黄原酮由于其平面结构而被公认为有效的葡萄糖苷酶抑制剂,从而为研究人员利用其设计和开发用于抗糖尿病治疗的强效新型杂交黄原酮打开了大门。本研究旨在用烟酰胺和链脲佐菌素(60mg/kg i.p.)诱导糖尿病大鼠,测定和评估不同合成的羟基黄酮衍生物的抗糖尿病潜力。将部分纯化的合成羟基黄酮衍生物,即A1、A2、A3、A4和A5,以150mg/kg的剂量,每次口服(p.o.)给糖尿病大鼠,并研究该部分对血糖水平的影响,直至21天。此外,对合成的化合物进行光谱分析以进行表征。硅分子对接结果表明,化合物A3显示出最佳的结合能得分。此外,合成羟基黄酮衍生物的体内抗糖尿病潜力表明,与标准药物米格利托相比,化合物A3和A2在控制血糖水平方面显著有效。此外,发现化合物A3和A2在链脲佐菌素诱导的Wistar大鼠模型中对恢复肝脏酶和脂质图谱有效。为了研究用于预测生物活性的化合物,发现羟基黄色葡萄球菌具有毒性的安全裕度,并在开发潜在的α-葡萄糖苷酶抑制剂方面发挥主导作用。这些化合物在对接结果、合成数据和体内抗糖尿病活性之间显示出极好的相关性。然而,可以进行进一步的修饰以增强效力、结合亲和力并将毒性降至最低。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
In-silico design,synthesis and evaluation of hydroxyxanthone derivatives as potential anti-diabetic agents targeting α - glucosidase
Glucosidase is a catalytic enzyme that catalyzes, specifically hydrolyses, the carbohydrates to free glucose units in blood in the last step of carbohydrate metabolism. So far, many compounds with α-glucosidase inhibitory activity for example, acarbose, voglibose etc., have been accounted and commercialized for diabetes therapy. However, Xanthones are recognized as efficient glucosidase inhibitors because of their planar structure and thereby opens the door for the researchers to utilize the same for designing and developing potent and novel hybrid xanthones for anti-diabetic therapy. The current study aimed to determine and evaluate the anti-diabetic potential of different synthetic hydroxylxanthone derivatives using Nicotinamide and Streptozotocin(60mg/kg i.p.) induced diabetic rats. The partially purified synthetic hydroxyxanthone derivatives namely A1,A2, A3, A4, and A5 were administered to diabetic rats with a dose of 150mg/kg, per oral(p.o.) and the effect of the fraction on blood glucose level was studied upto 21 days. Further, the synthetic compounds were subjected to spectral analysis for their characterization. The in-silico molecular docking results indicated that the compound A3 has shown the best binding energy score. Also, the in-vivo anti-diabetic potential of the synthetic hydroxyxanthone derivatives have revealed that the compounds A3 and A2 were significantly effective in controlling the blood glucose level when compared to the standard drug miglitol. In addition, compounds A3 and A2 were found to be effective in restoring the enzymes of liver and lipid profile in Streptozotocin-induced Wistar rat models. With an objective to investigate the compounds for predicting biological activity, it was found that the hydroxyxanthonepossesses a safety margin for toxicity and acts as a lead towards the development of potential α-glucosidase inhibitors. These compounds show excellent correlation between docking results, synthetic data and in-vivo anti-diabetic activity. However, further modifications can be done to enhance the potency, binding affinity profile and minimize toxicity.
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来源期刊
Current Enzyme Inhibition
Current Enzyme Inhibition Pharmacology, Toxicology and Pharmaceutics-Drug Discovery
CiteScore
1.30
自引率
0.00%
发文量
30
期刊介绍: Current Enzyme Inhibition aims to publish all the latest and outstanding developments in enzyme inhibition studies with regards to the mechanisms of inhibitory processes of enzymes, recognition of active sites, and the discovery of agonists and antagonists, leading to the design and development of new drugs of significant therapeutic value. Each issue contains a series of timely, in-depth reviews written by leaders in the field, covering a range of enzymes that can be exploited for drug development. Current Enzyme Inhibition is an essential journal for every pharmaceutical and medicinal chemist who wishes to have up-to-date knowledge about each and every development in the study of enzyme inhibition.
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