Computational investigation to identify multi-targeted anti-hyperglycemic potential of substituted 2-Mercaptobenzimidazole derivatives and synthesis of new α-glucosidase inhibitors

IF 3 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Tanya Waseem, Muhammad Kazim Zargaham, Madiha Ahmed, Tausif Ahmed Rajput, Adnan Amin, Humaira Nadeem
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引用次数: 0

Abstract

One of the most widespread diseases recognized all over the world is diabetes, accounting for 1.5 million deaths each year. Recent studies have demonstrated benzimidazole derivatives as potential antidiabetic agents. Hence, the present study is focused on designing new derivatives of 2-mercaptobenzimidazole by C-S cross-coupling reaction and are subjected to computational screening to identify the most promising candidate. Molecular docking and MM-GBSA calculations were performed to ascertain the binding potential with different antidiabetic targets, including α-glucosidase, PPaR-γ, DPP-4, and AMPK. We observed somewhat moderate binding interactions of the synthesized compound against the α-glucosidase. Since binding affinities can be improved using synthetic chemistry approaches, synthesis of analogues (A-18a-c) by designing hybrids at sites such as the acidic functionality of A-18 was done. The analogue A-18a, with p-fluorobenzyl substitution, exhibited enhanced binding affinity (-4.339 Kcal/mol) with the α-glucosidase compared to the parent compound (-3.827 Kcal/mol). The synthesized analogues were also subjected to an in-vitro α-glucosidase inhibitory assay. Among them, A-18a exhibited the most significant inhibitory potential, with an IC50 value of 0.521 ± 0.01 µM as compared to the standard drug Acarbose (IC50 21.0 ± 0.5 µM). This aligns with the computational study findings, where A-18a exhibited stronger binding interactions within the active site of the enzyme. Hence, a promising analogue of the designed compound was synthesized through a computationally guided approach as an anti-hyperglycaemic agent. Additionally, most of the designed compounds showed significantly greater binding affinity with PPaR-γ as compared to the standard pioglitazone. A-18 was successfully synthesized by S-arylation reaction using CuI in 89% yield and was subjected to MD-simulation against PPaR-γ, which revealed stable binding throughout the 200 ns run. Future studies will focus on exploring the activity of the designed drugs against PPaR-γ through in-vitro and in-vivo assays.

Graphical Abstract

Graphical depiction of flow of study starting from drug designing and followed by the prediction of molecular targets, ligand binding and molecular dynamics.

取代的2-巯基苯并咪唑衍生物多靶点降糖潜能的计算研究及新型α-葡萄糖苷酶抑制剂的合成
全世界公认的最普遍的疾病之一是糖尿病,每年造成150万人死亡。最近的研究表明,苯并咪唑衍生物是潜在的降糖药。因此,本研究的重点是通过C-S交叉偶联反应设计新的2-巯基苯并咪唑衍生物,并进行计算筛选,以确定最有希望的候选物。通过分子对接和MM-GBSA计算确定其与不同降糖靶点(包括α-葡萄糖苷酶、PPaR-γ、DPP-4和AMPK)的结合势。我们观察到合成的化合物对α-葡萄糖苷酶有一定程度的结合相互作用。由于结合亲和性可以通过合成化学方法来提高,因此通过在A-18的酸性官能团等位点设计杂化物来合成类似物(A-18a-c)。与母体化合物(-3.827 Kcal/mol)相比,对氟苯取代的类似物A-18a与α-葡萄糖苷酶的结合亲和力(-4.339 Kcal/mol)增强。合成的类似物也进行了体外α-葡萄糖苷酶抑制实验。其中A-18a表现出最显著的抑制电位,IC50值为0.521±0.01µM,而标准药物阿卡波糖的IC50值为21.0±0.5µM。这与计算研究结果一致,其中A-18a在酶的活性位点内表现出更强的结合相互作用。因此,设计的化合物的有前途的类似物被合成通过计算引导的方法作为抗高血糖剂。此外,与标准吡格列酮相比,大多数设计的化合物与PPaR-γ的结合亲和力显著提高。通过s -芳基化反应,以89%的产率成功合成了A-18,并对PPaR-γ进行了md模拟,结果表明A-18在200 ns内稳定结合。未来的研究将集中在通过体外和体内试验探索设计的药物对PPaR-γ的活性。从药物设计到分子靶点预测、配体结合和分子动力学的研究流程的图形描述。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Computer-Aided Molecular Design
Journal of Computer-Aided Molecular Design 生物-计算机:跨学科应用
CiteScore
8.00
自引率
8.60%
发文量
56
审稿时长
3 months
期刊介绍: The Journal of Computer-Aided Molecular Design provides a form for disseminating information on both the theory and the application of computer-based methods in the analysis and design of molecules. The scope of the journal encompasses papers which report new and original research and applications in the following areas: - theoretical chemistry; - computational chemistry; - computer and molecular graphics; - molecular modeling; - protein engineering; - drug design; - expert systems; - general structure-property relationships; - molecular dynamics; - chemical database development and usage.
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