CAJ | 학술논문

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 - X 2.1.1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 q2=0.578，回归系数 r2=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。
병형병독성간염감염시수혈후간염적주요병인지일。NS5A 단백적소분자억제제현시출흔강적체외억제병독생장적활성，병차초보적림상평개야증실료 NS5A 억제제능흔호지억제체내병형간염병독적생장。인차，연발고효적 NS5A 소분자억제제위치료병형간염제공료신적책략。진행료 daclatasvir 병형간염병독 NS5A 복제억제제적삼유정량구효관계（3D-QSAR）연구，통과 SYBYL - X 2.1.1분자모의연건계통수심방법수심출화합물적최저능량구상，연후재 Triops 력장중용공액제도최소화진행우화。응용비교분자력장분석（CoMFA）화비교분자상사성지수분석（CoMSIA）진행분자활성구상적선택、분자첩합、건립공간장범위이급수거통계。용22개연생물작위훈련집건립모형，용6개연생물작위측시집래험증모형적우렬。결과표명：CoMFA 모적교차상호험증계수 q2=0.578，회귀계수 r2=0.939，CoMSIA 모형적 q2=0.584， r2=0.968。저사결론위병형간염병독 NS5A 복합체억제제적약물설계화사선제공료이론의거。
AbstraCt:Viral hepatitis C infection is one of the main causes of the hepatitis after blood transfusion. NS5A 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 NS5A inhibitors can inhibit the growth of hepatitis c virus in the body. Therefore,the research and development of efficient NS5A 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,and the r2 = 0. 968. These conclusions laid a reliable theoretical basis for drug design and screening of hepatitis C virus NS5A complex inhibitors.