Raj Ruhani, Parjapati Charu, Garg Minakshi, Kaur Anupreet
Department of Biotechnology, UIET, Panjab University, Chandigarh, India.
Curr Hypertens Rev. 2025;21(1):45-61. doi: 10.2174/0115734021328359241206073629.
Hypertension is a worldwide problem that affects people of all ethnicities and social groups. Its mortality rate has been steadily increasing. However, several pharmacological compounds have been used to manage hypertension and related issues. Calcium Channel Blockers (CCBs) based on Dihydropyridine (DHP) are used as first-line therapy. It is well established that simple adjustments to an existing medicine's fundamental structure can considerably improve its efficacy.
The purpose of this research study was to create potential antihypertensive drugs utilizing a 1,4-DHP scaffold and analyze their binding processes with different calcium channel proteins for comparative analysis, with PDB IDs 3LV3, 1T0J, and 6DAF. This study used molecular docking and ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) profiling to predict the binding efficacy of newly produced potential drugs, such as CCBs.
The binding energy of the protein with the newly created compounds ranged between -2.6 and -7.26 kcal/mol (3LV3), -7.42 to -10.36 kcal/mol (1T0J), and -6.63 to -11.98 kcal/mol (6DAF).
The predicted ADMET profiling yielded significant results, indicating that among the virtually prepared ligands, apart from the standard drugs amlodipine and nifedipine, ligand numbers 60 and 13 showed a favorable ADMET profile.
In this study, drug development efforts focused on modifying existing hypertension medications through analysis. From hundreds of synthesized ligands, 19 showed optimal docking scores. ADMET profiling of these 19 ligands revealed ligands 60 and 13 to have favorable profiles. The Swiss ADME and ADMET lab 2.0 tools confirmed these findings, highlighting their potential for further development.
高血压是一个全球性问题，影响着所有种族和社会群体的人群。其死亡率一直在稳步上升。然而，已有多种药物化合物用于治疗高血压及相关问题。基于二氢吡啶（DHP）的钙通道阻滞剂（CCB）被用作一线治疗药物。众所周知，对现有药物基本结构进行简单调整可显著提高其疗效。
本研究旨在利用1,4 - 二氢吡啶支架创建潜在的抗高血压药物，并分析它们与不同钙通道蛋白的结合过程以进行比较分析，这些钙通道蛋白的蛋白质数据银行（PDB）ID分别为3LV3、1T0J和6DAF。本研究使用分子对接和ADMET（吸收、分布、代谢、排泄、毒性）分析来预测新产生的潜在药物（如CCB）的结合效果。
新创建化合物与蛋白质的结合能在 -2.6至 -7.26千卡/摩尔（3LV3）、 -7.42至 -10.36千卡/摩尔（1T0J）以及 -6.63至 -11.98千卡/摩尔（6DAF）之间。
预测的ADMET分析产生了显著结果，表明在虚拟制备的配体中，除了标准药物氨氯地平和硝苯地平外，配体编号60和13显示出良好的ADMET特征。
在本研究中，药物开发工作集中于通过分析修改现有的高血压药物。从数百种合成配体中，有19种显示出最佳对接分数。对这19种配体的ADMET分析表明配体60和13具有良好的特征。瑞士ADME和ADMET lab 2.0工具证实了这些发现，突出了它们进一步开发的潜力。
