多发性硬化症是以中枢神经系统白质炎性脱髓鞘病变和神经元损伤为主要特征的自身免疫疾病。免疫系统CB2受体被认为是潜在治疗多发性硬化症药物研发的靶点。本项目拟基于由CB1晶体结构模建的CB2Homology模型，通过微秒或毫秒级长时间分子动力学模拟，和13CH3-Met标记CB2的NMR HSQC研究，探索配体结合于CB2作用模式和引起CB2活性态非活性态构象动态变化的分子机制，建立受体-配体相互作用指纹图谱。运用基于结构和基于配体的合理药物设计理论和技术，结合ADME/T预测，通过构效关系研究发展高活性成药性良好的CB2激动剂。通过CB2激动剂EAE小鼠模型的体内药效评价，研究其外周免疫应答、对淋巴细胞进入CNS的影响、和炎症因子等生物学机制，阐明CB2激动剂能有效降低MS病程中白细胞浸润和中枢神经系统脱髓鞘作用的理论基础，为CB2成为多发性硬化症药物研发靶点提供理论依据。

Multiple sclerosis is considered an autoimmune disease targeting the CNS with inflammatory lesions, demyelination, and axonal/neuronal damage. The CB2 receptor in immune system was regarded to be a potential target for the development of drug for multiple sclerosis. In this proposed project, we will perform long molecular dynamic simulations on unligand bound CB2 homology model, homology constructed using the crystal structure of CB1 receptor as a template, ligand-CB2 complex model in combined with HSQC spectra of 13CH3-Met labeled CB2 or its complex with agonist or inverse agonist to explore the interaction mode of ligand binding to CB2 and molecular mechanism of CB2 ligand induced dynamics of CB2 from inactive form and active form. By structure-based and ligand-based drug design and ADME/T prediction, structure-activity relationships studies will be carried out to developed high-potent CB2-selective agonist with good drugability. EAE mouse will be used to do in vivo activity test of CB2 agonist, and biological mechanism will be explored for CB2 agonist ability to decrease the level of demyelination by studying peripheral response. it will be expected to reveal that CB2 is a new target of drug development for multiple sclerosis.