半胱氨酸蛋白酶拟肽抑制剂设计新进展

半胱氨酸蛋白酶包括多种酶,这些酶在广泛的生命过程中发挥作用。人类正常的半胱氨酸蛋白酶表达失调,寄生虫、病毒的半胱氨酸蛋白酶表达与多种病理情况相关。对于这类疾病,抑制半胱氨酸蛋白酶是一个可行的药物治疗策略。当前这类药物设计的目标是3种结构不同的半胱氨酸蛋白酶,即木瓜蛋白酶家族、半胱氨酸-天冬氨基特异性蛋白酶家族(caspases)和小核糖核酸病毒科半胱氨酸蛋白酶抑制剂家族。本文综述了近年来有关半胱氨酸蛋白酶抑制剂的设计思路。     

分子对接在基于结构药物设计中的应用

分子对接是研究分子间（如配体如受体）相互作用,并预测其结合模式和亲合力的一种理论模拟方法。近年来,分子对接方法已成为计算机辅助药物研究领域的一项重要技术,在数据库搜寻,组合库设计及蛋白作用研究方面得到了广泛发展。     

重组人受体蛋白FKBP12与新型神经生长促进剂非共价键复合物的电喷雾质谱

系统地用电喷雾质谱(ESI-MS)研究了重组人受体蛋白FKBP12(rhFKBP12)和其小分子神经生长促进剂配体的非共价键相互作用, 从52个化合物中筛选出3个有非共价键结合的化合物000107, 000308和A2B12, 并通过竞争实验测定了它们与rhFKBP12的结合位点和相对结合强度. 清华大学对其中的两个000107, 000308做出了复合物X射线晶体衍射的三维结构, 与ESI-MS的结果相同, 其中000308有较好的促神经生长的活性.     

ESI-MS study on non-covalent bond complex of rhFKBP12 and new neurogrowth promoter

An ESI-MS method for studying the non-covalent bond complex of rhFKBP12 with its nonimmunosuppressive ligands was developed. The method was used to screen out three compounds capable of binding to rhFKBP12 non-covalently from 52 compounds. By competing binding experiment, the binding site and the relative binding strength of these three compounds 000107, 000308 and A2B12 with rhFKBP12 were measured. All of them have the same binding site as FK506 does. X-ray crystalline diffraction experiment of non-covalent bond complex of 000107, 000308 with rhFKBP12 by Tsinghua University showed the same results. Among them 000308 has good effect on stimulating neurite to grow in chicken sensory neuronal cultures.     

新型二氢嘧啶类化合物的合成及其抗乙型肝炎病毒活性研究

以芳香氰基化合物为起始原料,经胺解、乙酰化、催化氢化、关环等步骤得到新型二氢嘧啶类化合物14个,结构通过核磁共振氢谱、质谱、元素分析确证,并利用HepG2.2.15细胞进行了体外抗HBV活性评价.结果表明部分化合物具有明显的抗HBVDNA复制作用,其中化合物5c和5n抑制HBVDNA复制的半数有效浓度分别为0.87μmol/L和0.67μmol/L.初步探讨了活性化合物的构效关系,同时运用分子排阻色谱法考察了活性化合物与病毒衣壳蛋白的相互作用.     

ESI-MS study on non-covalent bond complex of rhFKBP12 and new neurogrowth promoter

The drug FK506 is a powerful immunosuppressive agent. FKBP12 which has a molecular weight of 12 kD is one of the important members of FK506 binding proteins[1]. After finding it in 1989 scientists began to study its role in mediating responses to immunosuppressant drugs[2—4]. In 1992, it was reported that the level of FKBP12 is 50-fold more abundant in nervous system than that in immune tissues and the immunosuppressive agent FK506 mediated by FKBP12 can pro-mote neurite outgrowth both…