Department of Dermatology, Hangzhou Third People's Hospital, Zhejiang Chinese Medical University, Hangzhou, People's Republic of China.
Lupus. 2020 Nov;29(13):1704-1711. doi: 10.1177/0961203320952541. Epub 2020 Aug 27.
Network pharmacology is used with bioinformatic tools to broaden the understanding of drugs' potential targets and the intersections with key genes of particular disease. Here we applied network pharmacology to collect testable hypotheses about the multi-targets mechanism of hydroxychloroquine (HCQ) against systemic lupus erythematosus (SLE).
Firstly, we predicted the potential targets of HCQ. Secondly, we got the related genes of SLE returned from databases. Thirdly, the intersections of the potential targets (HCQ) and related genes (SLE) were analyzed with gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Finally, we validated our predictions of the potential targets by performing docking studies with HCQ.
The results suggest that the efficacy of HCQ against SLE is mainly associated with the targets of cyclin-dependent kinase 2 (CDK2), estrogen receptor alpha (ESR1) and CDK1, which regulate PI3K/Akt/GSK3β as well as interferon (IFN) signaling pathway. Biological process of the network associated with the three targets is concentrated in the inhibition of immune response, negative regulation of gene expression and regulation of immune system process. Molecular docking analysis proves that hydrogen bonding and π-π stacking are the main forms of interaction.
Our research provides protein targets affected by HCQ in the treatment of SLE. Three key targets (CDK2, ESR1 and CDK1) involving 1766 proteins become the multi-targets mechanism of HCQ in the treatment of SLE. As well, the research also provides a new idea for introducing network pharmacology into the evaluation of the drugs with multi-targets in dermatology.
网络药理学结合生物信息学工具，拓宽了对药物潜在靶点的理解，并揭示了其与特定疾病关键基因的交集。本研究应用网络药理学收集了羟氯喹（HCQ）治疗系统性红斑狼疮（SLE）多靶点机制的可测试假说。
首先，我们预测了 HCQ 的潜在靶点。其次，我们从数据库中获得了与 SLE 相关的基因。然后，通过基因本体论（GO）和京都基因与基因组百科全书（KEGG）富集分析，对潜在靶点（HCQ）和相关基因（SLE）的交集进行了分析。最后，我们通过与 HCQ 进行对接研究来验证我们对潜在靶点的预测。
结果表明，HCQ 治疗 SLE 的疗效主要与细胞周期蛋白依赖性激酶 2（CDK2）、雌激素受体α（ESR1）和 CDK1 的靶点相关，这些靶点调节 PI3K/Akt/GSK3β 以及干扰素（IFN）信号通路。与三个靶点相关的网络的生物学过程主要集中在抑制免疫反应、负向调节基因表达和调节免疫系统过程。分子对接分析证明氢键和π-π堆积是主要的相互作用形式。
本研究提供了 HCQ 治疗 SLE 中受影响的蛋白质靶标。三个关键靶点（CDK2、ESR1 和 CDK1）涉及 1766 种蛋白质，成为 HCQ 治疗 SLE 的多靶点机制。此外，该研究还为将网络药理学引入皮肤科多靶点药物评价提供了新的思路。
