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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已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) are a type of transmembrane transporter widely distributed in the human body. MRPs can selectively and specifically transfer different structures of drugs, drug conjugates and metabolites and other small molecule compounds to the outside of cells to make the anti-cancer drugs clinically applicable. Therefore, accurately predicting molecular characteristics of transportable specific substrates of MRPs is of great significance for the development of anti-tumor drug resistance development. In this paper, substrate molecules that are known to be shared by the seven subtypes of MRPs (including MRP1, -2, -3, -4, -5, -6 and -8) and the entire family of MRPs are analyzed using CATALYST software , The pharmacophore model of each subtype of MRPs and the whole family was constructed based on the common features of the molecules. The bait molecules were generated by DUD-E to validate and select the pharmacophore model, and the most suitable pharmacophore model of AUC (area under curve) was selected to screen the human endogenous metabolic database (HMDB) A molecule has been verified by the literature. By comparing the physical properties (ALOGP, molecular polar surface, molecular volume, molecular mass, number of hydrogen bond acceptors and number of hydrogen bonding donor) of the screened molecule and the known substrate molecule to the structure backbone Analysis and found that both: 1) the two have a consistent distribution trend in ALOGP, molecular volume, molecular mass; 2) compared with other subtypes MRP1 substrate molecules have a higher fat solubility, which is MRP1 medicine There are two hydrophobic centers in the phased model; 3) Both have the same scaffolding structure or similar scaffolding in skeleton characteristics.