Wang Zhe, Chen Gaozhi, Chen Linfeng, Liu Xing, Fu Weitao, Zhang Yali, Li Chenglong, Liang Guang, Cai Yuepiao
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Mol Biosyst. 2015 Jul;11(7):1933-8. doi: 10.1039/c5mb00085h.
Curcumin, a natural product, has been shown to possess notable anti-inflammatory activities and numerous studies have been carried out on its clinical applications. Recently, several reports mentioned that myeloid differentiation protein 2 (MD-2) may be the direct target of curcumin in the inhibition of lipopolysaccharide (LPS) signaling. However, the exact interaction between curcumin and MD-2 is still incompletely understood. In the present study, computational and experimental methods were employed to explore the underlying structural mechanism of curcumin binding to the MD-2 protein. Molecular docking and molecular dynamics (MD) simulation studies showed that curcumin could be embedded into the hydrophobic pocket of MD-2 and form stable hydrogen bonding interactions with residues R90 and Y102 of MD-2. Moreover, experimental results of curcumin binding to the MD-2(R90A/Y102A) mutant further confirmed that residues ARG-90 and TYR-102 contribute to the recognition process of curcumin binding to the MD-2 protein. In conclusion, we have explored the binding mechanism of curcumin to MD-2; more importantly, this work could offer useful references for designing novel analogs of curcumin as potential anti-inflammatory agents targeting the MD-2 protein.
姜黄素是一种天然产物，已被证明具有显著的抗炎活性，并且已经对其临床应用进行了大量研究。最近，有几份报告提到髓样分化蛋白2（MD-2）可能是姜黄素抑制脂多糖（LPS）信号传导的直接靶点。然而，姜黄素与MD-2之间的确切相互作用仍未完全了解。在本研究中，采用计算和实验方法来探索姜黄素与MD-2蛋白结合的潜在结构机制。分子对接和分子动力学（MD）模拟研究表明，姜黄素可以嵌入MD-2的疏水口袋中，并与MD-2的R90和Y102残基形成稳定的氢键相互作用。此外，姜黄素与MD-2（R90A/Y102A）突变体结合的实验结果进一步证实，ARG-90和TYR-102残基有助于姜黄素与MD-2蛋白结合的识别过程。总之，我们探索了姜黄素与MD-2的结合机制；更重要的是，这项工作可为设计新型姜黄素类似物作为靶向MD-2蛋白的潜在抗炎剂提供有用的参考。
