中文摘要：

摘要：丙型病毒性肝炎感染是输血后肝炎的主要病因之一。NS5A蛋白的小分子抑制剂显示出很强的体外抑制病毒生长的活性，并且初步的临床评价也证实了NS5A抑制剂能很好地抑制体内丙型肝炎病毒的生长。因此，研发高效的Ns5A小分子抑制剂为治疗丙型肝炎提供了新的策略。进行了daclatasvir丙型肝炎病毒NS5A复制抑制剂的三维定量构效关系（3D．QSAR）研究，通过SYBYL—X2．1．1分子模拟软件系统搜寻方法搜寻出化合物的最低能量构象，然后在Triops力场中用共轭梯度最小化进行优化。应用比较分子力场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）进行分子活性构象的选择、分子叠合、建立空间场范围以及数据统计。用22个衍生物作为训练集建立模型，用6个衍生物作为测试集来验证模型的优劣。结果表明：CoMFA模的交叉相互验证系数q。=0．578，回归系数r。=0．939，CoMSIA模型的q2=0．584，r2=0．968。这些结论为丙型肝炎病毒NS5A复合体抑制剂的药物设计和筛选提供了理论依据。

英文摘要：

Viral hepatitis C infection is one of the main causes of the hepatitis after blood transfusion. NSSA protein of small molecule inhibitors shows strong activity in inhibiting the growth of the vitro vi- rus, and the preliminary clinical evaluation also confirmed that NSSA inhibitors can inhibit the growth of hepatitis c virus in the body. Therefore, the research and development of efficient NSSA small mol- ecule inhibitors provides a new strategy for the treatment of hepatitis C. In this study, we investigated the daclatasvir hepatitis C virus NS5A inhibitor complex 3D-QSAR, and searched out the lowest ener- gy conformations of compounds through SYBLE-X 2.1.1 molecular modeling software system search method, and then Triops force field conjugate gradient minimization optimization. Comparative Molec- ular Field Analysis （CoMFA） and Comparative Molecular Similarity Indices Analysis （CoMSIA） were used to have molecular active conformation selection, molecular alignment, as well as the establish- ment of spatial statistics field range. In this experiment, taking 22 derivatives as the training set to build the model, the merits of the model was validated with 6 derivatives as a test set. Results show that Cross CoMFA model＇ s mutual authentication factor q2 = 0. 578, and the regression coefficient r2 = 0. 939, while CoMSIA model q2 = 0. 584, theoretical basis for drug design and screening and the r2 = 0. 968. These conclusions laid a reliable of hepatitis C virus NS5A complex inhibitors.