CoMFA Analysis

Flexible 3D alignment of a set of ligands binding to the same target and/or CoMFA analysis allowing the perception of a pharmacophore for this target. 

Fig. 12.41 Contour representation of key features from a CoMFA analysis of a scries ofcoumarin substrates and inhibitors ofq/tochrome fPosn el al. 1995], T...

The variable selection methods have been also adopted for region selection in the area of 3D QSAR. For example, GOLPE [31] was developed with chemometric principles and q2-GRS [32] was developed based on independent CoMFA analyses of small areas of near-molecular space to address the issue of optimal region selection in CoMFA analysis. Both of these methods have been shown to improve the QSAR models compared to original CoMFA technique. 

Medvedev AE, Veselovsky AV, Shvedov VI, Tikhonova OV, Moskvitina TA, Fedotova OA, et al. Inhibition of monoamine oxidase by pirlindole analogues 3D-QSAR and CoMFA analysis. / Chem Inf Comput Sci 1998 38 1137-44. Miller JR, Edmondson DE. Structure-activity relationships in the oxidation of para-substituted benzylamine analogues by recombinant human liver monoamine oxidase A. Biochemistry 1999 38 13670-83. 

Diana GD, Kowalczyk P, Treasurywala AM, Oglesby RC, Pevear DC, Dutko FJ. CoMFA analysis of interactions of antipicornavirus compounds in the binding pocket of human rhinovirus-14. J Med Chem 1992 35 1002— 1008. 

Moron, J.A., Campillo, M., Perez, V., Unzeta, M., Pardo, L. Molecular determinants of MAO selectivity in a series of indolylmethylamine derivatives biological activities, 3D-QSAR/CoMFA analysis, and computational simulation of ligand recognition./. Med. Chem. 2000, 43, 1684-1691. 

Li AH, Moro S, Melman N, Ji XD, Jacobson KA (1998) Structure-activity relationships and molecular modelling of 3, 5-diacyl-2, 4-dialkylpyridine derivatives as selective A, adenosine receptor antagonists. J Med Chem 41 3186-3201 Li AH, Moro S, Forsyth N, Melman N, Ji XD, Jacobson KA (1999) Synthesis, CoMFA analysis, and receptor docking of 3, 5-diacyl-2, 4-dialkylpyridine derivatives as selective A3 adenosine receptor antagonists. J Med Chem 42 706-721... 

Figure7.6 Steric favorable (green) and steric unfavorable fellow) interaction fields for a series of 131 propafenone analogues as revealed in a CoMFA analysis.

Godha, K., Mori, I., Ohta, D. and Kikuchi, T. (2000) A CoMFA analysis with conformational propensity an attempt to analyze the SAR of a set of molecules with different conformational flexibihty using a 3D-QSAR method. /. Comput. Aid. Mol. Des.,... 

Antimalarial activity of 4,5-secoartemisinins (51 1-4) which consisted of 1,2,4-trioxane with a lactone has been reported [53]. (-)-5-Nor-4,5-secoartemisinin (51 2, Rj = CH3> R2= H, R3= CH3) was as effective as artemisinin against the D-6 clone. The same analogs which were prepared by using the prediction in CoMFA analysis showed that the differences of activity were small between the predicted and actual values [41]. 

Because of this success, Carotti s group then carried out a QSERR and CoMFA analysis of a-alkyl-a-aryloxyacetic acid methyl esters, on the same CSP and then compared their results with those from the sulfoxide binding study described above... 

Fig. 12 41 Contour representation of key features from a CoMFA analysis of a senes of coumann substrates and inhibitors o cytochrome P glAS fPoso el al 1995] The red and blue regions indicate positions where it wnild he fnmi ahlp n id nnfnrnrnlle esperineh, fo place n p p , PfPgj, eo C - j. r k...

Note PRESS and q may relate to any property that is being modelled and not just activity , will always be smaller than r. When q > 0.3, a model is considered significant. Although cross-validation may seem a robust validation technique, some difficulties should not be overlooked. Variables that do not contribute to prediction, i.e. cause noise in the model, may have detrimental effects on CV. This may particularly play a role when many variables have to be considered, such as in a 3D-QSAR CoMFA analysis (see Chapter 25). A procedure for variable selection in the case of many variables has been developed and is named GOLPE (generating optimal linear PLS estimations). ... 

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