As a chronic inflammatory and angiogenic disease with increased morbidity and mortality, rheumatoid arthritis (RA) is characterized by the proliferation of synovial tissue and the accumulation of excessive mononuclear infiltration, which always results in the joint deformity, disability, and eventually the destruction of the bone and cartilage. Traditional Chinese Medicine (TCM), with rich history of proper effectiveness in treating the inflammatory joint disease containing RA, has long combated such illness from, actually, an integrative and holistic point of view. However, its “multi-components” and “multi-targets” features make it very difficult to decipher the molecular mechanisms of RA from a systematic perspective if employing only routine methods. Presently, an innovative systems-pharmacology approach was introduced, which combined the ADME screening model, drug targeting, and network pharmacology, to explore the action mechanisms of botanic herbs for the treatment of RA. As a result, we uncovered 117 active compounds and 85 key molecular targets from seven RA-related herbs, which are mainly implicated in four signaling pathways, that is, vascular endothelial growth factor, PI3K-Akt, Toll-like receptor, and T-cell-receptor pathways. Additionally, the network relationships among the active components, target proteins, and pathways were further built to uncover the pharmacological characters of these herbs. Besides, molecular dynamics (MD) simulations and molecular mechanics-Poisson–Boltzmann surface area calculations were carried out to explore the binding interactions between the compounds and their receptors as well as to investigate the binding affinity of the ligand to their protein targets. In vitro experiments by ligand binding assays validate the reliability of the drug–target interactions as well as the MD results. The high binding affinities and good inhibitions of the active compounds indicate that the potential therapeutic effects of these herbal medicines for treating RA are exerted probably through the modulation of these relevant proteins, which further validates the rationality and reliability of the drug-target interactions as well as our the network-based analytical methods. This work may be of help for not only understanding the action mechanisms of TCM and for discovering new drugs from plants for the treatment of RA, but also providing a novel potential method for modern medicine in treating complex diseases.

中文翻译：

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系统药物学解剖的多种作用机理的草药在类风湿关节炎的治疗

类风湿关节炎（RA）作为一种具有较高发病率和死亡率的慢性炎症和血管生成疾病，其特征在于滑膜组织的增生和过多的单核浸润的蓄积，这总是导致关节畸形，致残，并最终导致关节的破坏。骨骼和软骨。实际上，从综合和整体的角度来看，中医（TCM）在治疗包含RA的炎性关节疾病方面具有适当的有效历史，长期以来一直在与这种疾病作斗争。但是，如果仅采用常规方法，其“多组分”和“多靶点”特征使得很难从系统的角度来解读RA的分子机制。目前，引入了一种创新的系统-药理学方法，结合ADME筛选模型，药物靶向和网络药理学，探讨了植物药治疗RA的作用机制。结果，我们从7种与RA相关的草药中发现了117种活性化合物和85个关键分子靶标，它们主要与血管内皮生长因子，PI3K-Akt，Toll样受体和T-细胞受体途径。此外，还建立了活性成分，靶蛋白和途径之间的网络关系，以揭示这些草药的药理特性。除了，通过配体结合试验进行的体外实验验证了药物-靶标相互作用以及MD结果的可靠性。活性化合物的高结合亲和力和良好抑制作用表明，这些草药治疗RA的潜在治疗作用可能是通过调节这些相关蛋白来发挥的，这也进一步验证了药物-靶标相互作用的合理性和可靠性作为我们基于网络的分析方法。这项工作不仅可以帮助了解中药的作用机制，还可以从植物中发现用于治疗RA的新药，也为现代医学治疗复杂疾病提供了新的潜在方法。