Fu Min, Chen Lihui, Zhang Limin, Yu Xiao, Yang Qingrui
Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
Int J Mol Med. 2017 May;39(5):1164-1172. doi: 10.3892/ijmm.2017.2926. Epub 2017 Mar 20.
The control and treatment of rheumatoid arthritis is a challenge in today's world. Therefore, the pursuit of natural disease-modifying antirheumatic drugs (DMRDs) remains a top priority in rheumatology. The present study focused on curcumin and its derivatives in the search for new DMRDs. We focused on prominent p38 mitogen-activated protein (MAP) kinase p38α which is a prime regulator of tumor necrosis factor-α (TNF-α), a key mediator of rheumatoid arthritis. In the present study, we used the X-ray crystallographic structure of p38α for molecular docking simulations and molecular dynamic simulations to study the binding modes of curcumin and its derivatives with the active site of p38α. The ATP-binding domain was used for evaluating curcumin and its derivatives. Molecular docking simulation results were used to select 4 out of 8 compounds. These 4 compounds were simulated using GROMACS molecular simulation platform; the results generated were subjected to molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) calculations. The results showed cyclocurcumin as a potential natural compound for development of a potent DMRD. These data were further supported by inhibition of TNF-α release from lipopolysaccharide (LPS)-stimulated human macrophages following cyclocurcumin treatment.
类风湿性关节炎的控制和治疗是当今世界面临的一项挑战。因此，寻找天然的改善病情抗风湿药（DMRDs）仍然是风湿病学的首要任务。本研究聚焦于姜黄素及其衍生物，以寻找新型DMRDs。我们重点关注了突出的p38丝裂原活化蛋白（MAP）激酶p38α，它是肿瘤坏死因子-α（TNF-α）的主要调节因子，而TNF-α是类风湿性关节炎的关键介质。在本研究中，我们利用p38α的X射线晶体结构进行分子对接模拟和分子动力学模拟，以研究姜黄素及其衍生物与p38α活性位点的结合模式。ATP结合结构域用于评估姜黄素及其衍生物。分子对接模拟结果用于从8种化合物中筛选出4种。使用GROMACS分子模拟平台对这4种化合物进行模拟；对产生的结果进行分子力学-泊松玻尔兹曼表面积（MM-PBSA）计算。结果表明环姜黄素是开发强效DMRD的一种潜在天然化合物。环姜黄素处理后，脂多糖（LPS）刺激的人巨噬细胞中TNF-α释放受到抑制，进一步支持了这些数据。
