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QSAR - Hansch and Free Wilson Analyses

Hugo Kubinyi, - Hansch and free WilsonAnalysesHugo KubinyiGermanyE-Mail Kubinyi, GanellinProfessor ofMedicinal ChemistryUniversity College,London, UKS. L. Carney (DDT 9, 158-160 (2004)):Has there been a single development that, in your opinion, has moved the field of medicinal chemistry ahead more than any other?Robert Ganellin:I would go back to the 1960s to the work of Corwin Hansch on the impor-tance of lipophilicity.. I think that changed the way of thinking in medi-cinal chemistry.. I think that the application of physical organic chemical approaches to structure activity analysis have been very important. Hugo Kubinyi, XYBrNCH3CH3x HClmetaparalog 1/Cmetaparalog 1 Activities of meta-, para-, and meta,para- Disubstituted N,N-Dimethyl- -bromophenethylaminesHugo Kubinyi, (X)para(Y)log 1/Cobsd.

Hugo Kubinyi, www.kubinyi.de QSAR - Hansch and Free Wilson Analyses Hugo Kubinyi Germany E-Mail kubinyi@t-online.de HomePage www.kubinyi.de Hugo …

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Transcription of QSAR - Hansch and Free Wilson Analyses

1 Hugo Kubinyi, - Hansch and free WilsonAnalysesHugo KubinyiGermanyE-Mail Kubinyi, GanellinProfessor ofMedicinal ChemistryUniversity College,London, UKS. L. Carney (DDT 9, 158-160 (2004)):Has there been a single development that, in your opinion, has moved the field of medicinal chemistry ahead more than any other?Robert Ganellin:I would go back to the 1960s to the work of Corwin Hansch on the impor-tance of lipophilicity.. I think that changed the way of thinking in medi-cinal chemistry.. I think that the application of physical organic chemical approaches to structure activity analysis have been very important. Hugo Kubinyi, XYBrNCH3CH3x HClmetaparalog 1/Cmetaparalog 1 Activities of meta-, para-, and meta,para- Disubstituted N,N-Dimethyl- -bromophenethylaminesHugo Kubinyi, (X)para(Y)log 1/Cobsd.

2 +Esmetalog 1 1 forHanschAnalysisXYBrNCH3CH3x HClHugo Kubinyi, forFree Wilson Analysismeta paralog 1/C meta- para-log 1/C(X) (Y) obs. FClBr IMeFClBr HClHugo Kubinyi, Wilson Analysis, Results: = (n = 22; r = ; s = ) Hansch Analyses , Results:C. Hansch and E. J. Lien, Biochem. Pharmacol. 17, 709 (1968)log 1/C = - + (n = 22; r = ; s = )A. Cammarata, J. Med. Chem. 15, 573 (1972)log 1/C = ( ) m - ( ) m + ( ) rvpara + (n = 22; r = ; s = ) Kubinyi, Equationslog 1/C = ( ) - ( ) + + ( )(n = 22; r = ; s = ; F = )log 1/C = ( ) - ( ) + + ( ) Esmeta + ( )(n = 22; r = ; s = ; F = ) free Wilson Equationlog 1/C = - ( ) [m-F] + ( ) [m-Cl] + ( ) [m-Br] + ( ) [m-I] + ( ) [m-Me] + ( ) [p-F] + ( ) [p-Cl] + ( ) [p-Br] + ( ) [p-I] + ( ) [p-Me] + ( )(n = 22; r = ; s = ; F = )Hugo Kubinyi, AnalysisMathematically exact procedure for the treatment of data with experimental errors (cf.)

3 Mean value, standard devation). Minimization of the sum of squared errors (= squared deviations between yi and ycalc) produces the best fit of the observed values to a certain analysis describes the relationship between:- independent variables xi (definition: can be determined without experimental error), and- dependent variables yi (contain experimental error).Hypothesis: there is a significant relationship (95% level) between xi and yi values: yes / noF test for overall significancet tests for individual significances in multiple Kubinyi, and Meaning of Statistical ParametersCorrelation coefficient r (relative quality of fit)r2 = 1 - 2/Syy Standard deviation s (absolute quality of fit)s2 = 2/(n - k - 1) F test (Fisher value; level of statistical significance)F = r2.

4 (n - k - 1)/(k.(1 - r2))Confidence intervals of ki ciiHugo Kubinyi, Log 1/C = ( ) - ( ) + + ( ) (n = 22; r = ; s = ; F = ; Q = ; sPRESS = )C = molar concentration values of the 95% confidence intervalsthat causes a certain regression of the coefficients andbiological effect coefficients the constant termnumber ofcompoundscorrelation coefficient r; measure of the relative quality of a model Fisher value;measure of thestatistical significancelogarithms ofreciprocal values are lipophilicity electronic the correct scaling parameter parameter constanttermstandard deviation of crossvalidationpredictions andsquared crossvalidationregression coefficient;both are measures ofinternal predictivity standard deviation s; measure of the absolute quality of a modelHugo Kubinyi, YX} y95% confidence intervals of the regression line95% confidende intervals for a new observationregression lineRegression Analysis - A Common QSAR Toolhomogeneousdata ?

5 This is notan outlier !beware ofextrapolationcausalrelationship?Hugo Kubinyi, Sies, Nature 332, 495 (1988)The Storks and the BabiesHugo Kubinyi, = - = = = = = Important is a Graphical Analysis of the Data !Hugo Kubinyi, Diagram Tells You More Than Thousand EquationsAnil K. Saxena, Quant. Relat. 14, 142-150 (1995)183 Hydrocarbons, Alcohols, Ethers, Esters, Carboxylic Acids, Amines and Ketones MR vs. 1 r = ; s = ; F = MR vs. 2 vr = ; s = ; F = log P vs. 1 r = ; s = ; F = log P vs. 2 vr = ; s = ; F = P = ( ) 1 - ( ) I + ( )(n = 183; r = ; s = ; F = 4,633)Hugo Kubinyi, P and In = 183r = = = 4,633 HydrocarbonsAlcohols, Ethers, Esters,Carboxylic Acids, Aminesand KetonesHugo Kubinyi, Activity of Homologous Aliphatic Aminesvs.

6 Rhinocladium beurmanni(E. J. Lien and P. H. Wang, J. Pharm. Sci. 69, 648-650 (1980))Parabolic Model, log Pr = ; s = ; F = Model and log MW termr = ; s = ; F = 1/C = log P - log ( + 1)- (n = 15; r = ; s = ; F = 7,401)Hugo Kubinyi, unicorns, beasts that exist on paper but not in reality (C. Hansch , 1973):sinus functionshyperbolic functionstangens functions(for references cf. H. Kubinyi, QSAR: Hansch Analysis and Related Approaches, VCH, Weinheim, 1993) Antitumor Activity of Glutamic Acid AmidesT. Jha et al., Ind. J. Chem. 25B, 169-174 (1986)log % ITW = (log P)2 log P 2 Ali - Ali + Es Ali i + (n = 8; r = ; s = )R1SO2 NHCONHR2 HOOCHugo Kubinyi, fish 96-h LC50 (moles/L) = log Kow - , R2= <6, MW<1000log fish 96-h LC50 (millimoles/L) = - log Kow (CLOGP)n=2, R2= <6, MW<1000log fish 96-h LC50 (millimoles/L) = - log Kow (SRC)n=2, R2= <6, MW<1000log daphnid ChV (millimoles/L) = - log Kow (CLOGP)n=2, R2= <8, MW<1000log algal ChV (millimoles/L) = - log Kow (CLOGP)n=2, R2= <8, MW<1000log fish 96-h LC50 (mmoles/L) = + log Kow (CLOGP)n=3, R2= <6, MW<1000 Hugo Kubinyi, of Glycine Ester Amides to PapainC.

7 Hansch and D. F. Calef, J. Org. Chem. 41, 1240 (1976)C. Hansch et al., Arch. Biochem. Biophys. 183, 383 (1977)XHRNOOXRlog 1/Km MR Kubinyi, 1/Km MR (MR values scaled by a factor )Hugo Kubinyi, (n = 7) ( ) r = ; s = ; F = = ; s = ; F = r = ; s = ; F = ( ), MR ( )r = ; s = ; F = ( ), r = ; s = ; F = , r = ; s = ; F = 1/Km = ( ) MR + ( ) + ( )(n = 7; r = ; s = ; F = )Mesylamides (n = 13) ( ) r = ; s = ; F = = ; s = ; F = r = ; s = ; F = ( ), MRr = ; s = ; F = ( ), r = ; s = ; F = , r = ; s = ; F = 1/Km = ( ) MR + ( ) + ( )(n = 13; r = ; s = ; F = )RHNOOORHNOCH3SO2 OHugo Kubinyi, Compounds (n = 20)MR ( )r = ; s = ; F = ( )r =.

8 S = ; F = = ; s = ; F = ( ), ( )r = ; s = ; F = , Ir = ; s = ; F = , Ir = ; s = ; F = , , Ir = ; s = ; F = 1/Km = ( ) MR + ( ) - ( ) I + ( )(n = 20; r = ; s = ; F = ) log 1/Km = ( ) + (n = 16; r = ; s = )NOOONXHHugo Kubinyi, Ki = ( ) MR2 - ( ) log ( .10MR2 + 1) - ( )log = - optimum MR2 = (n = 19; r = ; s = )log Ki = ( ) MR2 - ( ) log ( .10MR2 + 1) + ( ) MR3 + ( ) *3 - ( ) I - ( )log = - optimum MR2 = (n = 53; r = ; s = )Inhibition of Chymotrypsin by ThiophosphonatesC. Silipo et al., Arch. Biochem. Biophys. 194, 552 (1979)Hugo Kubinyi, and Peripheral Activities of Clonidine AnalogsP. B. M. W. M. Timmermans et al., J. Med. Chem.

9 24, 502-507 (1981); J. Med. Chem. 27, 495 - 503 (1984)NNNClClHHLog Papp n-octanol / buffer pH central antihypertensive activity (molar dose that causes a 25% blood pressure decrease; anesthetized rat, application)C60 peripheral hypertensive activity (molar dose that causes a60 mm blood pressure increase; pithed rat, application)IC50 1 binding affinity to 1 receptors (replacement of prazosin)IC50 2 binding affinity to 2 receptors (replacement of clonidine)Hugo Kubinyi, Activity: Blood Pressure IncreasepC60 = ( ) pIC50 2 - (n = 21; r = ; s = )Central Activity: Blood Pressure DecreasepC25 = ( ) pIC50 2 + ( ) log P - ( ) log ( P + 1) - = log Popt = (n = 21; r = ; s = )Peripheral vs. Central Action on Blood PressurepC25 = ( ) pC60 + ( ) log P - ( ) log ( P + 1) - = log Popt = (n = 21; r = ; s = )Hugo Kubinyi, of Benzylpyrimidines to DHFRNNNH2NH2 XEscherichia coli DHFR log 1/Ki app = ( ) 3,4,5 - ( ) log (.)

10 10 3,4,5 + 1) + ( ) MR 3,5 + ( ) MR 4 + = = (n = 43; r = ; s = )Lactobacillus casei DHFR log 1/Ki app = ( ) 3,4 - ( ) log ( .10 + 1) + ( ) MR 3,4 + = - optimum = (n = 42; r = ; s = )Hugo Kubinyi, Mode of Trimethoprim to E . coli DHFR (Met-20)Hugo Kubinyi, Mode of Trimethoprim to L . casei DHFR (Leu-20)Hugo Kubinyi, Wilson AnalysesAntibacterial activity of phenols vs. Staphylococcus aureuslog 1/C = ( ) [Cl] + (n = 9; r = ; s = ; F = )Corticosteroid-binding globulin affinities of steroidslog 1/CBG = ( ) [ >C=C<] + ( )(n = 21; r = ; s = ; F = ; Q2 = ; sPRESS = )OHXX = H, ClR1OR2HR1R2 HOH317 Hugo Kubinyi, Inhibition by 2,4-Diaminopyrimidines log 1/C = ( ) I-1 + ( ) I-8 - ( ) I-9 + ( ) I-13 - ( ) I-15 + ( ) I-20 + ( ) + ( )(n = 105; r =.


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