Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China.
Molecules. 2019 Apr 27;24(9):1661. doi: 10.3390/molecules24091661.
P-glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance (MDR) in cancer cells. In order to enhance the uptake of chemotherapy drugs, larger amounts of P-gp inhibitors are required. Besides several chemically synthesized P-gp inhibitors, flavonoids as P-gp inhibitors are being investigated, with their advantages including abundance in our daily diet and a low toxicity. The cytotoxicity of daunorubicin (as a substrate of P-gp) to KB/MDR1 cells and the parental KB cells was measured in the presence or absence of flavonoids. A two-dimensional quantitative structure-activity relationship (2D-QSAR) model was built with a high cross-validation coefficient (Q) value of 0.829. Descriptors including vsurf_DW23, E_sol, Dipole and vsurf_G were determined to be related to the inhibitory activity of flavonoids. The lack of 2,3-double bond, 3'-OH, 4'-OH and the increased number of methoxylated substitutions were shown to be beneficial for the inhibition of P-gp. These results are important for the screening of flavonoids for inhibitory activity on P-gp.
P-糖蛋白（P-gp）是开发抑制剂以克服癌细胞多药耐药性（MDR）的治疗靶标。为了增强化疗药物的摄取，需要更多的 P-gp 抑制剂。除了几种化学合成的 P-gp 抑制剂外，还在研究黄酮类化合物作为 P-gp 抑制剂，其优点包括在我们的日常饮食中丰富且毒性低。在存在或不存在黄酮类化合物的情况下，测量了道诺霉素（作为 P-gp 的底物）对 KB/MDR1 细胞和亲本 KB 细胞的细胞毒性。建立了二维定量构效关系（2D-QSAR）模型，交叉验证系数（Q）值为 0.829。确定了包括 vsurf_DW23、E_sol、Dipole 和 vsurf_G 在内的描述符与黄酮类化合物的抑制活性有关。缺乏 2,3-双键、3'-OH、4'-OH 和增加的甲氧基取代数有利于抑制 P-gp。这些结果对于筛选具有抑制 P-gp 活性的黄酮类化合物非常重要。
