Design, Synthesis, Molecular Docking and in vitro Biological Evaluation of some Benzamide Derivatives as novel Glucokinase Activators

Q4 Pharmacology, Toxicology and Pharmaceutics

Current Enzyme Inhibition Pub Date : 2022-02-18 DOI:10.2174/1573408018666220218093451

A. A. Kazi, V. Chatpalliwar

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引用次数: 1

Abstract

Glucokinase (GK) is a cytoplasmic enzyme that metabolises glucose to glucose-6-phosphate and supports adjusting blood glucose levels within the normal range in humans. In pancreatic β-cells, it plays a leading role in governing the glucose-stimulated secretion of insulin, and in liver hepatocyte cells, it controls the metabolism of carbohydrates. GK acts as a promising drug target for treating patients with type 2 diabetes mellitus (T2DM). The present work has been designed to discover some novel substituted benzamide derivatives This work involved designing novel benzamide derivatives and their screening by docking studies to determine the binding interactions for the best-fit conformations in the binding site of the GK enzyme. Based on the results of docking studies, the selected molecules were synthesized and tested for in vitro GK enzyme assay. The structures of newly synthesized products were confirmed by IR, NMR, and mass spectroscopy. Amongst the designed derivatives, compounds 4c, 4d, 4e, 5h, 5j, 5l, 5m, 5n, 5p, and 5r have shown better binding energy than the native ligand present in the enzyme structure. The synthesized compounds were subjected to in vitro GK enzyme assay. Out of all, compounds 4c, 4d, 5h, 5l, and 5n showed more GK activation than control. From the present results, we have concluded that the synthesized derivatives can activate the human GK enzyme effectively, which can be helpful in the treatment of T2DM.

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新型葡萄糖激酶激活剂苯甲酰胺衍生物的设计、合成、分子对接及体外生物学评价

葡萄糖激酶（GK）是一种细胞质酶，可将葡萄糖代谢为葡萄糖-6-磷酸，并支持将人体血糖水平调节在正常范围内。在胰腺β细胞中，它在控制葡萄糖刺激的胰岛素分泌中发挥主导作用，在肝细胞中，控制碳水化合物的代谢。GK是治疗2型糖尿病（T2DM）患者的一个很有前途的药物靶点。本工作旨在发现一些新的取代苯甲酰胺衍生物。这项工作涉及设计新的苯甲酰胺衍生品，并通过对接研究进行筛选，以确定GK酶结合位点中最适合构象的结合相互作用。基于对接研究的结果，合成了选定的分子，并对其进行了体外GK酶测定。通过红外光谱、核磁共振谱和质谱确证了新合成产物的结构。在设计的衍生物中，化合物4c、4d、4e、5h、5j、5l、5m、5n、5p和5r显示出比酶结构中存在的天然配体更好的结合能。对合成的化合物进行体外GK酶测定。其中，化合物4c、4d、5h、5l和5n表现出比对照更多的GK活化。从目前的结果来看，我们得出结论，合成的衍生物可以有效地激活人GK酶，这有助于治疗T2DM。

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来源期刊

Current Enzyme Inhibition Pharmacology, Toxicology and Pharmaceutics-Drug Discovery

CiteScore

1.30

自引率

0.00%

发文量

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.