Quantitative Structure-activity Relationship And Molecular Design Based On Anticancer Activity

Chapter one: Introduction.The computer aided drug design,this paper mainly introduces the application of QSAR methods,structure-activity relationship and molecular density functional theory of holographic quantitative 2D-QSAR,3D-QSAR Co MFA,Topomer Co MFA,Co MSIA,molecular docking,pharmacophore and virtual screening.The main work of the paper is to establish a structure-activity relationship of anticancer molecules pancreatic cancer and breast cancer by using these structure-activity relationship methods,analyze the main factors which influence their biological activities,guides new molecules design with highly activity and provides theoretical basis for synthetic works.Chapter two: Molecular docking and 3D-QSAR study of anticancer drugs ?,?-unsaturated carbonyl-based compounds.It has been found that ?,?-unsaturated carbonyl-based compounds have certain inhibitory effects on pancreatic cancer cells.In this chapter,31 ?,?-unsaturated carbonyl-based compounds were studied by Co MFA and Co MSIA,and a reliable model was established.The q2 values were 0.687 and 0.756,respectively,which explains the structure activity relationship of compounds from 5 field(steric field,electrostatic field,hydrophobic field,hydrogen donor donor field and hydrogen bond acceptor field).By structural modification of No.8 molecule,11 new drug molecules were designed.The effect of ?,?-unsaturated carbonyl-based compounds and pattern of Keap1 protein was investigated by using the molecular docking method,and the score of compound 28 is 7.0287,it isfound that the methoxy group and Keap1 receptor protein interacts with peripheral amino acid residues also produced electrostatic interaction,hydrophobic interaction.Chapter three: Based on Topomer Co MFA,Co MSIA,HQSAR method,the quantitative structure-activity relationship of heat shock protein(Hsp90)inhibitors was studied.According to the literature,Hsp90 inhibitors have an inhibitory effect on human breast cancer.This chapter uses Topomer Co MFA,Co MSIA and HQSAR three methods for constructing model of 44 novel inhibitor of heat shock protein 90,and their q2 were 0.660,0.688,0.769,respectively.Topomer Co MFA two field(steric and electrostatic field),Co MSIA optimal combination of three field(field,electrostatic field,hydrogen bond acceptor stereo field)are studied in the research activity contribution plot three dimensional contour map and HQSAR,and discusses the influencing factors of the inhibitory activity.Combined with three models,the structure of compound 37 molecule was optimized and 5 new Hsp90 inhibitors were designed.Chapter four: Molecular docking,virtual screening,QSAR and molecular design of anticancer heat shock protein(Hsp90)inhibitors.In this chapter,40 Hsp90 inhibitors are docking with the receptor protein 5GGZ to understand the interaction patterns between them.Among them,the molecules with better activity 35 were used to establish pharmacophore,and the highest molecular number 30 was scored by 10.4650 according to the docking score.16 potential heat shock protein inhibitors were screened out from 9 natural products database.Finally,the QSAR equation is established,and the chemical parameters of the equation are analyzed,(including LR3-C,EHOMO,and ?QB)?According to the results of the analysis of the pharmacophore and the 2D-QSAR model,the molecule of compound 35 was modified and four new molecules were designed.Chapter five: The study of the quantitative structure-activity relationship of benzylsulfonic derivatives PAIB-SOs by DFT.Based on quantum chemical density functional theory(DFT)and base group 6-31+G(D,P)level,40 benzene sulfonic acid derivatives PAIB-SOs molecules were optimized for structure and frequency calculation.According to the relevant formula and literature,20 groups of parameters were obtained.The main factors which affects the activity of anti human breast cancer were screened by stepwise regression analysis,and the effect equation was established.Finally,four new highly activity molecules were designed.