Design, Synthesis and Simulation Laboratory, Department of Chemistry, Raiganj University, 733134, WB, India.
Department of Chemistry, Government General Degree College at Kushmandi, Dakhin Dinajpur, 733121, West Bengal, India.
Curr Comput Aided Drug Des. 2024;20(7):1130-1146. doi: 10.2174/0115734099273719231005062524.
People of all nationalities and social classes are now affected by the growing issue of hypertension. Over time, there has been a consistent rise in the fatality rate. A range of therapeutic compounds, on the other hand, are often used to handle hypertension.
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.
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 ligand were calculated using the M06-2X/ def2- TZVP level of theory. The SwissADME website was used to study the ADMET properties.
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.
Based on molecular docking, molecular dynamics simulations, and drug-likeness properties of compound 16 can be used as a potential calcium channel blocker.
现在，各个国家和社会阶层的人都受到高血压这一日益严重问题的影响。随着时间的推移，死亡率一直在持续上升。另一方面，经常使用一系列治疗化合物来处理高血压。
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，其次是分析配体的类药性并研究其与 Cav1.2 模型蛋白结合的分子机制，最后是合成最佳配体。
由于缺乏人类 Cav1.2 的 3D 结构，因此使用同源建模方法对蛋白质结构进行建模。使用分子对接和分子动力学技术研究蛋白质-配体复合物的强度和结合相互作用。使用 M06-2X/def2-TZVP 理论水平计算配体的基于 DFT 的电子性质。使用 SwissADME 网站研究 ADMET 性质。
在这项研究中，我们设计了一系列 DHP 化合物（19 种化合物）作为钙通道阻滞剂。在这些化合物中，化合物 16 表现出优异的结合评分（-11.6 kcal/mol）。该化合物具有良好的产率并进行了表征。为了评估合成分子的结构特征，进行了量子化学计算。
基于分子对接、分子动力学模拟和化合物 16 的类药性，可以将其用作潜在的钙通道阻滞剂。
