Mansouri Pegah, Mansouri Pardis, Najafipour Sohrab, Kouhpayeh Seyed Amin, Farjadfar Akbar, Behmard Esmaeil
Student Research Committee, Fasa University of Medical Sciences, Fasa, Iran.
Department of Medical Biotechnology, Fasa University of Medical Sciences, Fasa, Iran.
Sci Rep. 2025 Jul 28;15(1):27516. doi: 10.1038/s41598-025-12666-4.
Rheumatoid arthritis (RA) is one of the most common inflammatory diseases in the world. Due to this importance, several drugs have been produced against effective targets in the pathogenesis of the disease. Considering various inflammatory pathways involved in RA, targeting each of these pathways alone cannot achieve sufficient improvement of the patients. Therefore, this study aimed to introduce safe natural product drug candidates screened in silico against several important protein targets (multi-targets) in the pathogenesis of RA. Tyrosine kinase 2 is a member of the Janus Kinase family, and due to its role in the signaling of numerous cytokines, its inhibition is considered an effective treatment option in inflammatory diseases. IL-6 is one of the most important innate immune cytokines that is secreted from activated macrophages in RA, and its level is directly related to the severity of joint destruction. Therefore, its inhibition plays an important role in improving the symptoms of RA. Also, the severity of the disease is directly related to the level of ACPA in the serum and synovial fluid of patients. Therefore, inhibiting its production by precluding the differentiation of B lymphocytes into plasma cells can improve the disease. In this study, after Virtual Screening, Molecular Docking, and Molecular Dynamics, we introduced Rutaecarpine, Hecogenin, Angustine, and Vomicine as new drug candidates for the treatment of RA. Rutaecarpine, Hecogenin, and Angustine inhibit all three targets with high affinity and stability, while Vomicine inhibits both TYK2 and IL-6 but not CD20. Future experimental studies can verify these findings.
类风湿性关节炎（RA）是世界上最常见的炎症性疾病之一。鉴于其重要性，已经研发出了多种针对该疾病发病机制中有效靶点的药物。考虑到RA涉及多种炎症途径，仅针对这些途径中的每一种进行靶向治疗并不能使患者得到充分改善。因此，本研究旨在介绍通过计算机模拟筛选出的针对RA发病机制中几个重要蛋白质靶点（多靶点）的安全天然产物候选药物。酪氨酸激酶2是Janus激酶家族的成员，由于其在多种细胞因子信号传导中的作用，其抑制被认为是炎症性疾病的一种有效治疗选择。白细胞介素-6是最重要的先天性免疫细胞因子之一，由RA中活化的巨噬细胞分泌，其水平与关节破坏的严重程度直接相关。因此，抑制白细胞介素-6在改善RA症状方面起着重要作用。此外，疾病的严重程度与患者血清和滑液中抗环瓜氨酸肽抗体（ACPA）的水平直接相关。因此，通过阻止B淋巴细胞分化为浆细胞来抑制其产生可以改善病情。在本研究中，经过虚拟筛选、分子对接和分子动力学研究，我们介绍了吴茱萸次碱、海柯皂苷元、狭叶番泻碱和吴茱萸胺作为治疗RA的新候选药物。吴茱萸次碱、海柯皂苷元与狭叶番泻碱以高亲和力和稳定性抑制所有三个靶点，而吴茱萸胺抑制酪氨酸激酶2和白细胞介素-6，但不抑制CD20。未来的实验研究可以验证这些发现。
