论文部分内容阅读
多药耐药相关蛋白(Multidrug resistance-associated proteins,MRPs)是在人体广泛分布的一类跨膜转运蛋白.MRPs可选择性和特异性地将不同结构的药物、药物结合物及代谢物和其他的小分子化合物转到细胞外,使临床应用的抗肿瘤药物产生耐药性.因此,准确预测MRPs可转运的特异性底物分子特征,对于抗肿瘤药物的抗耐药性研发具有重要意义.本文利用MRPs的7个亚型(包括MRP1,-2,-3,-4,-5,-6和-8)已知的底物分子和MRPs整个家族共同转运的底物分子,应用CATALYST软件,基于分子共同特征分别构建了MRPs各亚型和整个家族的药效团模型.并利用DUD-E生成诱饵分子用于验证和选取药效团模型,选择AUC (area under curve)打分最好的药效团模型对人体内源性代谢数据库(HMDB)进行筛选,筛选获得的多个分子得到了文献的验证.通过对药效团筛选出的分子和己知的底物分子进行物理性质(ALOGP、分子极性表面、分子体积、分子质量、氢键受体数和氢键给体数)和结构骨架的比较分析,发现两者∶1)两者在ALOGP、分子体积、分子质量上具有一致的分布趋势;2)与其他亚型相比,MRP1的底物分子具有较高的脂溶性,这与MRP1药效团模型中具有两个疏水中心相一致;3)两者在骨架特征上,具有相同的骨架结构或相似的骨架片段.“,”Multidrug resistance-associated proteins (MRPs) can efflux structurally diverse drugs,drug conjugates,drug metabolites,as well as other small molecules out of the cells,and this is the main cause of producing multidrug resistance (MDR) of some anticancer drugs.Therefore,it is crucial to uncover the molecular features of MRPs substrates in developing anti-MDR cancer therapy.In the present study,common feature pharmacophore models were developed by employing CATALYST Pharmacophore Modeling and Analysis tools using substrates of MRPs,including MRP1,-2,-3,-4,-5,-6,-8 and MRPs family,respectively.The models were validated using independent decoy sets generated in DUD-E,and the ones with best AUC (area under the curve)scores were chosen to predict endogenous substrates by screening the Human Metabolome Database (HMDB).A number of molecules obtained by pharmacophore screening have been validated in the literatures.By comparing physical properties (ALOGP,Molecular_PolarSurfaceArea,Molecular_Volume,Molecular_Weight,Num H Acceptors,Num H Donors) and scaffold features of the screened candidates with the known substrates,we found that:1) The two sets have consistent ALOGP,Molecule_Volume and Molecule_Weight distribution trend;2) Substrates of MRP1 have a better lipophilicity than the other subtypes,which is consistent with the two hydrophobic centers on the MRP1 pharmacophore;3) In the aspect of the scaffold structures,they have the identical or similar backbone fragments.