基于网络药理学和分子对接的归脾汤治疗抑郁症的药效机制研究。
The Mechanisms Underlying the Pharmacological Effects of GuiPi Decoction on Major Depressive Disorder based on Network Pharmacology and Molecular Docking.
机构信息
Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
出版信息
Comb Chem High Throughput Screen. 2023;26(9):1701-1728. doi: 10.2174/1386207325666220831152959.
BACKGROUND AND AIM
Major Depressive Disorder (MDD) is a common affective disorder. GuiPi decoction (GPD) is used to treat depression in China, Japan, and Korea. However, its effective ingredients and antidepressant mechanisms remain unclear. We attempted to reveal the potential mechanisms of GPD in the treatment of MDD by network pharmacology and molecular docking. In addition, we conducted an enzymatic activity assay to validate the results of molecular docking.
METHODS
GPD-related compounds and targets, and MDD-related targets were retrieved from databases and literature. The herb-compound-target network was constructed by Cytoscape. The protein- protein interaction network was built using the STRING database to find key targets of GPD on MDD. Enrichment analysis of shared targets was analyzed by MetaCore database to obtain the potential pathway and biological process of GPD on MDD. The main active compounds treating MDD were screened by molecular docking. The PDE4s inhibitors were screened and verified by an enzyme activity assay.
RESULTS
GPD contained 1222 ingredients and 190 potential targets for anti-MDD. Possible biological processes regulated by GPD were neurophysiological processes, blood vessel morphogenesis, Camp Responsive Element Modulator (CREM) pathway, and Androgen Receptor (AR) signaling crosstalk in MDD. Potential pathways in MDD associated with GPD include neurotransmission, cell differentiation, androgen signaling, and estrogen signaling. Fumarine, m-cresol, quercetin, betasitosterol, fumarine, taraxasterol, and lupeol in GPD may be the targets of SLC6A4, monoamine oxidase A (MAOA), DRD2, OPRM1, HTR3A, Albumin (ALB), and NTRK1, respectively. The IC50 values of trifolin targeting Phosphodiesterase (PDE) 4A and girinimbine targeting PDE4B1 were 73.79 μM and 31.86 μM, respectively. The IC50 values of girinimbine and benzo[a]carbazole on PDE4B2 were 51.62 μM and 94.61 μM, respectively.
CONCLUSION
Different compounds in GPD may target the same protein, and the same component in GPD can target multiple targets. These results suggest that the effects of GPD on MDD are holistic and systematic, unlike the pattern of one drug-one target.
背景与目的
重度抑郁症（MDD）是一种常见的情感障碍。在中国、日本和韩国，桂皮汤（GPD）被用于治疗抑郁症。然而，其有效成分和抗抑郁机制仍不清楚。我们试图通过网络药理学和分子对接来揭示 GPD 治疗 MDD 的潜在机制。此外，我们进行了酶活性测定来验证分子对接的结果。
方法
从数据库和文献中检索 GPD 相关化合物和靶点以及 MDD 相关靶点。使用 Cytoscape 构建草药-化合物-靶标网络。使用 STRING 数据库构建蛋白质-蛋白质相互作用网络，以找到 GPD 治疗 MDD 的关键靶标。使用 MetaCore 数据库对共享靶标的富集分析，获得 GPD 治疗 MDD 的潜在途径和生物学过程。通过分子对接筛选治疗 MDD 的主要活性化合物。通过酶活性测定筛选和验证 PDE4s 抑制剂。
结果
GPD 含有 1222 种成分和 190 个抗 MDD 的潜在靶点。GPD 可能调节的可能的生物学过程包括神经生理学过程、血管形态发生、Camp 反应元件调节剂（CREM）途径和 MDD 中的雄激素受体（AR）信号转导。与 GPD 相关的 MDD 潜在途径包括神经递质、细胞分化、雄激素信号和雌激素信号。GPD 中的富马酸、间甲酚、槲皮素、β-谷甾醇、富马酸、蒲公英甾醇和羽扇豆醇可能分别是 SLC6A4、单胺氧化酶 A（MAOA）、DRD2、OPRM1、HTR3A、白蛋白（ALB）和 NTRK1 的靶点。三氟醇靶向磷酸二酯酶（PDE）4A 的 IC50 值和吉尼定靶向 PDE4B1 的 IC50 值分别为 73.79 μM 和 31.86 μM。吉尼定和苯并[a]咔唑对 PDE4B2 的 IC50 值分别为 51.62 μM 和 94.61 μM。
结论
GPD 中的不同化合物可能靶向相同的蛋白质，而 GPD 中的相同成分可以靶向多个靶标。这些结果表明，GPD 对 MDD 的影响是整体和系统的，而不是一种药物一种靶标的模式。
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