Design, In Silico Screening, Synthesis, Characterisation and DFT-based Electronic Properties of Dihydropyridine-based Molecule as L-type Calcium Channel Blocker

IF 1.5 4区医学 Q4 CHEMISTRY, MEDICINAL

Current computer-aided drug design Pub Date : 2023-12-27 DOI:10.2174/0115734099273719231005062524

Sujoy Karmakar, Hriday Kumar Basak, Uttam Paswan, Soumen Saha, Samir Kumar Mandal, Abhik Chatterjee

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引用次数: 0

Abstract

Objective: The objectives of this study are first to design potential antihypertensive drugs based on the DHP scaffold, secondly, to analyse drug-likeness properties of the ligands and investigate their molecular mechanisms of binding to the model protein Cav1.2 and finally to synthesise the best ligand. Methods: Due to the lack of 3D structures for human Cav1.2, the protein structure was modelled using a homology modelling approach. A protein-ligand complex's strength and binding interaction were investigated using molecular docking and molecular dynamics techniques. DFT-based electronic properties of the ligands were calculated using the M06-2X/ def2-TZVP level of theory. The SwissADME website was used to study the ADMET properties. Results: In this study, a series of DHP compounds (19 compounds) were properly designed to act as calcium channel blockers. Among these compounds, compound 16 showed excellent binding scores (-11.6 kcal/mol). This compound was synthesised with good yield and characterised. To assess the structural features of the synthesised molecule quantum chemical calculations were performed. Conclusion: Based on molecular docking, molecular dynamics simulations, and drug-likeness properties of compound 16 can be used as a potential calcium channel blocker.

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作为 L 型钙通道阻滞剂的二氢吡啶类分子的设计、硅学筛选、合成、表征和基于 DFT 的电子特性

研究目的本研究的目的首先是基于 DHP 支架设计潜在的抗高血压药物，其次是分析配体的药物相似性并研究其与模型蛋白 Cav1.2 结合的分子机制，最后是合成最佳配体。研究方法由于缺乏人Cav1.2的三维结构，因此采用同源建模方法对蛋白质结构进行建模。利用分子对接和分子动力学技术研究了蛋白质-配体复合物的强度和结合相互作用。使用 M06-2X/ def2-TZVP 理论水平计算了配体的 DFT 电子特性。使用 SwissADME 网站研究了 ADMET 特性。研究结果本研究适当设计了一系列 DHP 化合物（19 个化合物）作为钙通道阻滞剂。在这些化合物中，化合物 16 显示出优异的结合分数（-11.6 kcal/mol）。该化合物的合成收率很高，并已定性。为了评估合成分子的结构特征，对其进行了量子化学计算。结论：基于分子对接、分子动力学模拟和药物相似性，化合物 16 可用作一种潜在的钙通道阻滞剂。

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来源期刊

Current computer-aided drug design 医学-计算机：跨学科应用

CiteScore

3.70

自引率

5.90%

发文量

审稿时长

>12 weeks

期刊介绍： Aims & Scope Current Computer-Aided Drug Design aims to publish all the latest developments in drug design based on computational techniques. The field of computer-aided drug design has had extensive impact in the area of drug design. Current Computer-Aided Drug Design is an essential journal for all medicinal chemists who wish to be kept informed and up-to-date with all the latest and important developments in computer-aided methodologies and their applications in drug discovery. Each issue contains a series of timely, in-depth reviews, original research articles and letter articles written by leaders in the field, covering a range of computational techniques for drug design, screening, ADME studies, 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 etc., providing excellent rationales for drug development.