基于3D-药效团的P糖蛋白和细胞色素P4503A4的协同作用机理研究

P糖蛋白(P-glycoprotein,Pgp)和细胞色素P4503A4(CYP3A4)是决定药物ADME性质的两个重要蛋白,目前还无法通过实验方法,从分子水平清晰阐明这两个蛋白采取怎样的互补作用机理来降低外来药物的生物利用度.通过3D-药效团模建方法,提取Pgp和CYP3A4的共同底物的特征阐明这两个蛋白可能的协同作用模式.所得的药效团有助于理解药物分子同这两个蛋白的作用模式,同时该模型可以指导新药设计和改造,从而提高药物的生物利用度.

Study of concerted mechanism between P-glycoprotein and cytochrome P4503A4 by 3D-pharmacophore modeling

Various ongoing preclinical and clinical studies have demonstrated that P-glycoprotein(Pgp) and Cytochrome P4503A4(CYP3A4) offer dominant obstacles in reducing the systemic bioavailability of xenobiotics and cause the major drug-drug interaction.Presently the cause and mechanism of these two enzymes still remain difficult to determine,since their broad-spectrum tolerance to compounds with a great diversity results in their similar substrate binding or recognition pattern.Pgp and CYP3A4 share significant overlapping substrate specificity,thus a group of compounds that have been well identified as the Pgp and CYP3A4 overlapping substrates may possibly have the same substratebinding model with both enzymes may provide further understanding in investigating the molecular mechanisms.In this report,we describe two 3D-pharmacophores for both Pgp and CYP3A4 that possibly offer the common interacting models with the substrates.The application of this method allows the high throughput screening for compounds less likely to be transported by Pgp and also metabolized by CYP3A4.