Department of Pharmaceutical Technology, University College of Engineering, Bharathidasan Institute of Technology Campus, Anna University, Tiruchirappalli, 620 024, Tamil Nadu, India.
Appl Biochem Biotechnol. 2023 Nov;195(11):7037-7059. doi: 10.1007/s12010-023-04451-8. Epub 2023 Mar 28.
Rheumatoid arthritis (RA) is one of the most severe inflammatory diseases that cause swelling, stiffness and pain in the joints, which pose a significant threat worldwide. Damage-associated molecular patterns (DAMPs) are danger molecules of endogenous origin, released during cell injury or cell death, interacts with various Pattern recognition receptors (PRRs) and activates various inflammatory diseases. One of the DAMP molecules, so-called EDA-fibronectin (Fn) is also responsible for causing RA. EDA-Fn triggers RA through its interaction with TLR4. Apart from TLR4, it is divulged that certain other PRR's are also responsible for RA, but the identity and mechanism of those PRRs remain unknown until now. Hence, for the first time, we tried to reveal those PRR's interaction with EDA-Fn in RA through computational methods. Protein-protein interaction (PPI) was checked using ClusPro between EDA-Fn and certain Pattern recognition receptors (PRRs) to explore the binding affinities of the potential PRRs. Protein-protein docking unveiled that TLR5, TLR2 and RAGE has good interaction with EDA-Fn than the well-reported TLR4. Macromolecular simulation was performed for TLR5, TLR2 and RAGE complexes along with the control group TLR4 for 50 ns to further investigate the stability, leading to the identification of TLR2, TLR5 and RAGE as the stable complexes. Hence, TLR2, TLR5 and RAGE on interaction with EDA-Fn may lead to the progression of RA that may need additional validations through in vitro and in vivo animal models. Molecular docking was used to analyse the binding force of the top 33 active anti-arthritic compounds with the target protein EDA-Fn. Molecular docking study showed that withaferin A has a good binding activity with EDA-fibronectin target. Hence, it is emphasized that guggulsterone and berberine could modulate the EDA-Fn-mediated TLR5/TLR2/RAGE pathways, thereby it could inhibit the deteriorating effects of RA which needs further in vitro and in vivo experimental validations.
类风湿关节炎（RA）是一种最严重的炎症性疾病，可导致关节肿胀、僵硬和疼痛，在全球范围内构成重大威胁。损伤相关分子模式（DAMPs）是内源性起源的危险分子，在细胞损伤或死亡时释放，与各种模式识别受体（PRRs）相互作用并激活各种炎症性疾病。DAMP 分子之一，所谓的 EDA-纤维连接蛋白（Fn）也负责引起 RA。EDA-Fn 通过与 TLR4 的相互作用引发 RA。除了 TLR4，据透露，某些其他 PRR 也与 RA 有关，但这些 PRR 的身份和机制至今仍不清楚。因此，我们首次尝试通过计算方法揭示 RA 中 EDA-Fn 与这些 PRR 的相互作用。使用 ClusPro 检查 EDA-Fn 与某些模式识别受体（PRRs）之间的蛋白质-蛋白质相互作用（PPI），以探索潜在 PRR 的结合亲和力。蛋白质-蛋白质对接揭示 TLR5、TLR2 和 RAGE 与 EDA-Fn 的相互作用优于报道良好的 TLR4。对 TLR5、TLR2 和 RAGE 复合物以及对照组 TLR4 进行了 50ns 的大分子模拟，以进一步研究稳定性，从而确定 TLR2、TLR5 和 RAGE 为稳定复合物。因此，TLR2、TLR5 和 RAGE 与 EDA-Fn 的相互作用可能导致 RA 的进展，这可能需要通过体外和体内动物模型进行进一步验证。分子对接用于分析 33 种活性抗关节炎化合物与靶蛋白 EDA-Fn 的结合力。分子对接研究表明，吴茱萸内酯 A 与 EDA-纤维连接蛋白靶标具有良好的结合活性。因此，强调了古卡斯特酮和小檗碱可以调节 EDA-Fn 介导的 TLR5/TLR2/RAGE 途径，从而可以抑制 RA 的恶化作用，这需要进一步的体外和体内实验验证。
