Antitumor Activity And Molecular Design Dased On Tubulin

In this paper,the antitumor activity and molecular design of tubulin tumor inhibitors with colchicine binding sites were studied by computer-aided drug molecular design.Based on colchicine binding site tubulin,virtual screening,2D-QSAR,3D-QSAR and molecular docking methods were used to study prostate cancer and breast cancer inhibitors.The methods of virtual screening,QSAR and molecular docking play an important role in the discovery and optimization of lead compounds.Chapter one: introduction.The anticancer target of tubulin and its anticancer mechanism were introduced.Introduces the research methods of computer-aided drug molecular design,also.The current situation and some related targets of prostate cancer and breast cancer were analyzed.Chapter two: Virtual screening of FDA database with colchicine tubulin(1sa0)as the target.Analyze the results of virtual screenring.The cell activities of pradaxa,ritonavir and fosinopril which are considered to be valuable for further study.The IC50 values of PC-3,MCF-7 and T47 D were measured by MTT method.The results showed that pradaxa and ritonavir had good inhibitory effects on these three kinds of cancer cells.Fosinopril had inhibitory effect on PC-3,but almost no inhibitory effect on MCF-7 and T47 D.This research is beneficial to the development of new uses of old drugs.Chapter three: Curcuminoids breast cancer inhibitors were studied by 3D-QSAR model.CoMFA and CoMSIA models were used to analyze the relationship between structure and activity of 37 compounds.Molecular docking was used to assist analysis.Twelve new molecules were designed by modifying the molecule 15 with the best activity.The predicted activity of these 12 new molecules in both models was higher than that of molecule 15.Chapter four: 33 curcuminoids breast cancer inhibitors were studied by 2D-QSAR.B3 LYP / 6-31G(d,p)was used to calculate DFT of molecular density function in Gaussian 09.The alculated structural parameters,such as dipole moment,maximum occupied orbital energy,bond length and bond angle,were analyzed by multiple linear regression.The equation with inhibitor activity value as dependent variable and molecular structure parameter as independent variable was constructed.According to the equation,the relationship between structure and activity is obtained.Chapter five: In order to make up for the shortcomings of 2D-QSAR model in Chapter 4 and improve the accuracy of the model,3D-QSAR study was carried out on these 33 curcuminoids breast cancer inhibitors by Topomer CoMFA and CoMSIA models.Combined with the 2D-QSAR model in Chapter 4,Modified highest activity molecule 09.Two higher activity molecules were designed.