Quantitative Structure-Activity Relationships (QSAR)课件.ppt

Quantitative Structure-Activity Relationships (QSAR) ;QSAR: Systematic approach to lead compound optimization;Applications of QSAR(Hansch Analysis);Sulmazole;Hammett electronic parameter or substituent constant, s;Positive versus negative s values for chemical substituents, x.;Example of resonance forms that stabilize the negatively charged carboxylate in p-nitrobenzoic acid;General utility of ? values:Saponification of substituted ethyl benzoates ;The Hammett constants, s,, can be related to the free energy of ionization via the vant Hoff relationship (In this case s would correspond to the equilibrium constant, K, allowing for Hammett relationships to also be referred to as a linear free energy relationship (LFER)). ;Ester hydrolysis reaction and equation used to define the Taft steric parameter, Es ;Equation for the molar refractivity ;Consideration of asymmetric shape of functional groups and molecules in QSAR;Application of QSAR to biological systems (Biological Hammett Relationship):Hansch, 1962;Equations for the determination of the partition coefficient, P, and the hydrophobicity parameter, px ;Determination of partition coefficient, P ;Example of calculation of log P ;Example of a linear equation where multiple variables are used to obtain a correlation with biological activity (1/C). ;Multiple Regression AnalysisHypothetical training set of biological activities, hydrophobicities and sigma values ;Individual plots of log(1/C) versus p or s, including least-squares analysis ;Example of multiple regression least squares fitting;Application of multiple regression to the training set;Multiple regression alonestill didn’t work!;Log P versus biological activity(y = -x2) parabolic plot ;Hansch equation ;Example of an extended Hansch Equation where the Taft steric parameter, Es, has been included. ;Advantages of Hansch analysis;Disadvantages of Hansch analysis;QSAR interpolations versus extrapolations;Statistical Significance in QSAR;Free and Wilson Mode