从分子对接和动力学的综合角度出发，结合临床研究探讨直接口服抗凝剂对心房颤动中抗动脉粥样硬化蛋白的影响。
A comprehensive insight from molecular docking and dynamics with clinical investigation on the impact of direct oral anticoagulants on atheroprotective protein in atrial fibrillation.
机构信息
Drug Discovery and Multi-omics Laboratory, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, 603103, India.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.
出版信息
BMC Pharmacol Toxicol. 2024 Aug 22;25(1):56. doi: 10.1186/s40360-024-00785-z.
BACKGROUND
Direct oral anticoagulants (DOACs) have high potency against their therapeutic target and are widely used in the treatment of atrial fibrillation (AF). Most DOACs are often claimed to have adverse effects due to off-target inhibition of essential proteins. Human serum paraoxonase 1 (PON1), one of the essential proteins, known for its anti-inflammatory and antioxidant properties, could be affected by DOACs. Thus, a comparative evaluation of DOACs and their effect on PON1 protein will aid in recommending the most effective DOACs for AF treatment. This study aimed to assess the impact of DOACs on PON1 through a combination of computational and experimental analyses.
METHODS
We focus on apixaban, dabigatran, and rivaroxaban, the most recommended DOACs in AF treatment, for their impact on PON1 through molecular docking and molecular dynamics (MD) simulation to elucidate the binding affinity and drug-protein structural stability. This investigation revealed the most influential DOACs on the PON1 protein. Then experimental validation was performed in DOAC-treated AF participants (n = 42; 19 treated with dabigatran and 23 treated with rivaroxaban) compared to a healthy control group (n = 22) through gene expression analysis in peripheral blood mononuclear cells (PBMC) and serum enzyme concentration.
RESULTS
Our computational investigation showed rivaroxaban (-4.24 kcal/mol) exhibited a lower affinity against the PON1 protein compared to apixaban (-5.97 kcal/mol) and dabigatran (-9.03 kcal/mol) through molecular docking. Dabigatran holds complex interactions with PON1 at GLU53, TYR197, SER193, and ASP269 by forming hydrogen bonds. Additionally, MD simulation revealed that dabigatran disrupts PON1 stability, which may contribute functional changes. Further experimental validation revealed a significant down-regulation (p < 0.05) of PON1 gene expression in PBMC and decreased serum PON1 enzyme concentration on DOAC treatment. Rivaroxaban as about 48% has inhibitory percentage and dabigatran as about 75% of inhibitory percentage compared to healthy control.
CONCLUSION
Overall, our computational and experimental results clearly show the higher inhibitory effect of dabigatran than rivaroxaban. Hence, rivaroxaban will be a better drug candidate for improving the outcome of AF.
背景
直接口服抗凝剂（DOACs）对其治疗靶点具有高效性，广泛用于治疗心房颤动（AF）。由于对必需蛋白的非靶向抑制，大多数 DOACs 通常被认为具有不良反应。人血清对氧磷酶 1（PON1）是一种必需蛋白，具有抗炎和抗氧化特性，可能会受到 DOACs 的影响。因此，对 DOACs 及其对 PON1 蛋白的影响进行比较评估，将有助于推荐 AF 治疗中最有效的 DOACs。本研究旨在通过计算和实验分析相结合，评估 DOACs 对 PON1 的影响。
方法
我们专注于阿哌沙班、达比加群和利伐沙班，这三种 DOACs 是 AF 治疗中最推荐的药物，通过分子对接和分子动力学（MD）模拟研究它们对 PON1 的影响，以阐明结合亲和力和药物-蛋白结构稳定性。这项研究揭示了对 PON1 蛋白影响最大的 DOACs。然后，通过外周血单核细胞（PBMC）和血清酶浓度的基因表达分析，在 DOAC 治疗的 AF 参与者（n=42；19 例接受达比加群治疗，23 例接受利伐沙班治疗）与健康对照组（n=22）中进行了实验验证。
结果
我们的计算研究表明，与阿哌沙班（-5.97 kcal/mol）和达比加群（-9.03 kcal/mol）相比，利伐沙班（-4.24 kcal/mol）与 PON1 蛋白的亲和力较低。通过分子对接，达比加群与 PON1 上的 GLU53、TYR197、SER193 和 ASP269 形成氢键，具有复杂的相互作用。此外，MD 模拟表明，达比加群破坏了 PON1 的稳定性，这可能导致功能发生变化。进一步的实验验证表明，在 DOAC 治疗后，PBMC 中 PON1 基因表达显著下调（p<0.05），血清 PON1 酶浓度降低。与健康对照组相比，利伐沙班的抑制率约为 48%，达比加群的抑制率约为 75%。
结论
总的来说，我们的计算和实验结果清楚地表明，达比加群对 PON1 的抑制作用高于利伐沙班。因此，利伐沙班将成为改善 AF 预后的更好药物候选物。
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