Ahmed Emad A, Abdelsalam Salah A
Department of Biological Sciences, College of Science, King Faisal University, Hofouf 31982, Saudi Arabia.
Lab of Molecular Physiology, Zoology Department, Faculty of Science, Assiut University, Assiut 71516, Egypt.
Curr Issues Mol Biol. 2024 Sep 23;46(9):10635-10650. doi: 10.3390/cimb46090631.
A treasure trove of naturally occurring biomolecules can be obtained from sea living organisms to be used as potential antioxidant and anti-inflammatory agents. These bioactive molecules can target signaling molecules involved in the severity of chronic autoimmune diseases such as rheumatoid arthritis (RA). The intracellular tyrosine kinases family, Janus kinases (JAKs, includes JAK1, JAK2, and JAK3), is implicated in the pathogenesis of RA through regulating several cytokines and inflammatory processes. In the present study, we conducted molecular docking and structural analysis investigations to explore the role of a set of bioactive molecules from marine sources that can be used as JAKs' specific inhibitors. Around 200 antioxidants and anti-inflammatory molecules out of thousands of marine molecules found at the Comprehensive Marine Natural Products Database (CMNPD) website, were used in that analysis. The details of the interacting residues were compared to the recent FDA approved inhibitors tofacitinib and baricitinib for data validation. The shortlisted critical amino acids residues of our pharmacophore-based virtual screening were LYS905, GLU957, LEU959, and ASP1003 at JAK1, GLU930 and LEU932 at JAK2, and GLU905 and CYS909 of JAK3. Interestingly, marine biomolecules such as Sargachromanol G, Isopseudopterosin E, Seco-Pseudopterosin, and CID 10071610 showed specific binding and significantly higher binding energy to JAK1 active/potential sites when being compared with the approved inhibitors. In addition, Zoanthoxanthin and Fuscoside E bind to JAK2's critical residues, GLU930 and LEU932. Moreover, Phorbaketal and Fuscoside E appear to be potential candidates that can inhibit JAK3 activity. These results were validated using molecular dynamics simulation for the docked complexes, JAK1(6sm8)/SG, JAK2 (3jy9)/ZAX, and JAK3 (6pjc)/Fuscoside E, where stable and lower binding energy were found based on analyzing set of parameters, discussed below (videos are attached). A promising role of these marine bioactive molecules can be confirmed in prospective preclinical/clinical investigations using rheumatoid arthritis models.
可以从海洋生物中获取大量天然存在的生物分子，用作潜在的抗氧化剂和抗炎剂。这些生物活性分子可以作用于与类风湿性关节炎（RA）等慢性自身免疫性疾病严重程度相关的信号分子。细胞内酪氨酸激酶家族，即 Janus 激酶（JAKs，包括 JAK1、JAK2 和 JAK3），通过调节多种细胞因子和炎症过程参与 RA 的发病机制。在本研究中，我们进行了分子对接和结构分析研究，以探索一组海洋来源的生物活性分子作为 JAKs 特异性抑制剂的作用。在综合海洋天然产物数据库（CMNPD）网站上发现的数千种海洋分子中，约 200 种抗氧化剂和抗炎分子被用于该分析。将相互作用残基的详细信息与美国食品药品监督管理局（FDA）最近批准的抑制剂托法替布和巴瑞替尼进行比较以进行数据验证。基于药效团的虚拟筛选中入围的关键氨基酸残基在 JAK1 上是 LYS905、GLU957、LEU959 和 ASP1003，在 JAK2 上是 GLU930 和 LEU932，在 JAK3 上是 GLU905 和 CYS909。有趣的是，与已批准的抑制剂相比，海洋生物分子如 Sargachromanol G、异伪蕨素 E、裂环伪蕨素和 CID 10071610 对 JAK1 活性/潜在位点表现出特异性结合且结合能显著更高。此外，藻黄素和岩藻糖苷 E 与 JAK2 的关键残基 GLU930 和 LEU932 结合。而且，短裸甲藻毒素和岩藻糖苷 E 似乎是可以抑制 JAK3 活性的潜在候选物。使用对接复合物 JAK1(6sm8)/SG、JAK2 (3jy9)/ZAX 和 JAK3 (6pjc)/岩藻糖苷 E 的分子动力学模拟对这些结果进行了验证，基于下文讨论的一组参数（附上了视频）发现它们具有稳定且较低的结合能。在使用类风湿性关节炎模型的前瞻性临床前/临床研究中，可以证实这些海洋生物活性分子具有广阔的应用前景。
