基于花生四烯酸模型的滇产木姜子源植物抗炎物质基础和作用机制研究

Inflammation is a crucial physiological response of our body to any kind of noxa be it an infection or tissue injury. However, this physiological process can be detrimental if dysregulated, and when the acute inflammatory response fails to resolve the cause of inflammation, there can be a switch to chronification. For the treatment of inflammation, non-steroidal anti-inflammatory drugs (NSAIDs) are the most widespread drugs while glucocorticoids are among our strongest weapons against inflammation, making them emergency treatments for acute episodes of chronic inflammation. For the treatment of many inflammatory disorders, both are not satisfying. Consequently, industrial and academic research on anti-inflammatory drugs is very intensive. As the pathophysiological knowledge of diseases increased over the last decades, a more specific intervention of inflammatory pathways becomes possible. Interference with the arachidonic acid cascade is one of the most important approaches to treat inflammation. COX and 5-LOX are the crucial anti-inflammatory targets for drug discovery. Litsea plants have been used as folk medicines on inflammation-related therapy for a long time．However, the research on anti-inflammatory ingredients and quality standards of the plants is almost empty．This study aimed to evaluate the ability of the small molecules from Litsea plants to inhibit above enzyme activities by in silico docking studies and bioassays in vitro and in vivo. On the basis of above bioinformatics investigations, we will further combine in silico and bioassay approaches to obtain highly anti-inammatory small molecules from Litsea-derived natural compounds, furthermore to illuminate the underlying anti-infammatory mechanisms of action.

炎症是临床常见病理过程，抗炎药物是临床上仅次于抗感染药物的第二大类药物。花生四烯酸及其代谢产物在炎症中起着重要作用。前期我们利用已分离的木姜子源化合物为配体进行虚拟筛选，分子对接及活性筛选结果显示木姜子源化合物结合活性均较高，是发现抗炎活性分子的重要源泉。本项目拟借助合理药物设计的思路，根据传统用药经验选择具有抗炎作用的木姜子源药用植物，以木姜子源化合物为研究对象，结合虚拟筛选技术对木姜子源化合物进行类药性评价。建立基于COX及5-LOX的体外筛选和整体动物模型，开展高通量筛选，揭示木姜子源植物抗炎物质基础。通过药理实验和虚拟筛选结果进行综合评价，开展构效关系和作用机制研究。以发现的活性化合物为探针，开展化学生物学研究，探讨抗炎物质结构－生物活性相关性，为抗炎药物研究与应用提供科学依据

炎症是对多种有害刺激的防御和保护性反应,是多种炎性疾病发病机制的基础，抗炎新药的研究和开发意义重大。花生四烯酸是参与炎症反应的必需脂肪酸，环氧合酶、脂氧合酶是花生四烯酸代谢的关键酶，催化花生四烯酸生成重要的炎症介质前列腺素和白三烯，与慢性炎症性疾病密切相关，并且参与了肿瘤、动脉硬化、糖尿病和神经疾病等多种病理过程。本项目通过基于花生四烯酸系统的木姜子源植物化学成分抗炎的虚拟筛选研究和体外体内抗炎筛选研究，揭示了木姜子源植物分子具有明确的抗炎作用，初步阐明了木姜子源植物的抗炎活性的药效物质基础。研究结果支持了传统用药经验，它有希望成为临床用于治疗炎症的药物或先导化合物，值得开展进一步研究，深入揭示其作用机制，以发现抗炎新药。同时新骨架和新化合物的发现丰富了植物化学的内容，为木姜子源植物的化学分类学提供了科学依据，活性化合物的发现可作为先导化合物有助于指导有效化合物的合成和结构改造，并为深入研究和开发利用木姜子源植物奠定了科学基础。