CoMFA

Before the comparative molecular field analysis (CoMFA), BCUT descriptors, 4D-QSAR, and HYBOT descriptors arc discussed in more detail, some further descriptors are listed briefly. 

After an alignment of a set of molecules known to bind to the same receptor a comparative molecular field analysis CoMFA) makes it possible to determine and visuahze molecular interaction regions involved in hgand-receptor binding [51]. Further on, statistical methods such as partial least squares regression PLS) are applied to search for a correlation between CoMFA descriptors and biological activity. The CoMFA descriptors have been one of the most widely used set of descriptors. However, their apex has been reached. 

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 ability of partial least squares to cope with data sets containing very many x values is considered by its proponents to make it particularly suited to modern-day problems, where it is very easy to compute an extremely large number of descriptors for each compound (as in CoMFA). This contrasts with the traditional situation in QSAR, where it could be time-consuming to measure the required properties or where the analysis was restricted to traditional substituent constants. 

Cramer R D III, D E Patterson and J D Bunce 1988, Comparative Molecular Field Analysis (CoMFA). Effect of Shape on Binding of Steroids to Carrier Proteins. Journal of the American Chemical Societ 110 5959-5967. 

The biggest limitation of the CoMFA method is the alignment step. The algorithm superimposes the portions of the inhibitors that are of similar stmcture, assuming that they bind with similar orientations in the active site of the enzyme, which is not necessarily the case. Also, because of a problem with alignment, a CoMFA may fail when a few molecules are very dissimilar from all others in the series. Like QSAR, CoMFA does not require a stmcture of the relevant biological receptor, but does require knowledge about a series of inhibitory compounds. 

RD Cramer III, DE Patterson, JD Bunce. Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 110 5959-5967, 1988. 

T Kimura, K Hasegawa, K Funatsu. GA strategy for variable selection m QSAR studies GA-based region selection for CoMFA modeling. J Chem Inf Comput Sci 38 276-282, 1998. 

Among others, 11 was included in a series of drugs to study quantitative structure-activity relationships (96KFZ(6)29, 98MI7, 99BMC2437). A statistically significant CoMFA model was developed for describing the... 

Imidazolinyl) derivative of 8-methyl-2,3,6,7-tetrahydro-5 f- and 8-methyl-7-methoxy-5-oxo-2,3-dihydro-5 f-pyrido[l, 2, i-de]-1,4-benzoxazines were included in a 3D-QSAR CoMFA study on imidazolinergic I2 ligands (00JMC1109). 

Bis(oxazohnes) figands have been so widely used for the Diels-Alder reaction between N-2-alkenoyl-l,3-oxazolidine-2-one and cyclopentadiene that Lipkowitz and Pradhan developed a QSAR (quantitative structure-activity relationship) using Comparative Molecular Field Analysis (CoMFA) for a set of 23 copper-catalysts containing mainly bis(oxazoline) figands. The generated... 

DePriest SA, Mayer D, Naylor CB, Marshall GR. 3D-QSAR of angiotensinconverting enzyme and thermolysin inhibitors a comparison of CoMFA models based on deduced and experimentally determined active site geometries. J Am Chem Soc 1993 115 5372-84. 

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. 

Cavalli A, Greco G, Novellino E, Recanatini M. Linking CoMFA and protein homology models of enzyme-inhibitor interactions an application to nonsteroidal aromatase inhibitors. Bioorg Med Chem 2000 8 2771-80. 

Sipila J, Hood AM, Coughtrie MW, Taskinen J. CoMFA modeling of enzyme... 

A widely used 3-D QSAR method that makes use of PLS is comparative molecular field analysis (CoMFA), in which a probe atom is used to calculate the steric and electronic fields at numerous points in a 3D lattice within which the molecules have been aligned. Poso et al. [56] used the technique to model the binding of coumarins to cytochrome P450 2A5, with similar results to those obtained by Bravi and Wikel [55]. Shi et al. [57] used it to model the estrogen receptor binding of a large diverse set of compounds, and Cavalli et al. [58] used it to develop a pharmacophore for hERG potassium... 

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