Mosa Farag E S, C Suryanarayanan, Feng Tianhua, Barakat Khaled
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Ab, Canada.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Ab, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
J Mol Graph Model. 2021 Jan;102:107776. doi: 10.1016/j.jmgm.2020.107776. Epub 2020 Oct 22.
Selective calcium channel antagonists are widely used in the treatment of cardiovascular disorders. They are mainly classified into 1,4-dihydropyridine (1,4-DHPs) and non-DHPs. The non-DHPs class is further classified into phenylalkylamines (PAAs) and benzothiazepines (BZTs) derivatives. These blockers are used for the treatment of hypertension, angina pectoris, and cardiac arrhythmias. Despite their well-established efficiency, the structural basis behind their activity is not very clear. Here we report the use of a near-open confirmation (NOC) model of the Cav1.2 cardiac ion channel to examine the mode of binding of these antagonists within the pore domain as well as the fenestration of the pore-forming domains. Effects of calcium ion permeation in the presence of drug molecules were assessed using steered molecular dynamics (SMD) simulations. These studies reveal that nicardipine, a DHP derivative, shows a strong Cav1.2 blocking activity, requiring more 2500 pN force to pull calcium ion towards the channel's pore in the presence of the compound. Similar blocking activity was observed for verapamil, a PAA derivative, requiring almost 2300 pN of force. The least blocking activity was observed for Diltiazem, a BZT derivative. Our results explain the structural basis and the binding details of 1,4-DHPs, PAAs and BZTs at their distinct Cav1.2 sites and offer detailed insights into their mechanism of action in modulating the Cav1.2 channel.
选择性钙通道拮抗剂广泛应用于心血管疾病的治疗。它们主要分为1,4-二氢吡啶类（1,4-DHPs）和非二氢吡啶类。非二氢吡啶类又进一步分为苯烷基胺类（PAAs）和苯并硫氮杂䓬类（BZTs）衍生物。这些阻滞剂用于治疗高血压、心绞痛和心律失常。尽管它们的疗效已得到充分证实，但其活性背后的结构基础尚不完全清楚。在此，我们报告使用Cav1.2心脏离子通道的近开放构象（NOC）模型来研究这些拮抗剂在孔道结构域内的结合模式以及孔形成结构域的窗孔情况。使用引导分子动力学（SMD）模拟评估了药物分子存在时钙离子的渗透效应。这些研究表明，尼卡地平，一种二氢吡啶类衍生物，表现出很强的Cav1.2阻断活性，在该化合物存在的情况下，需要超过2500 pN的力才能将钙离子拉向通道孔。维拉帕米，一种苯烷基胺类衍生物，也观察到类似的阻断活性，需要近2300 pN的力。地尔硫䓬，一种苯并硫氮杂䓬类衍生物，观察到的阻断活性最小。我们的结果解释了1,4-二氢吡啶类、苯烷基胺类和苯并硫氮杂䓬类在其不同的Cav1.2位点的结构基础和结合细节，并为它们调节Cav1.2通道的作用机制提供了详细的见解。
