Limitations CoMFA

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. 

The popularity of commercial programs such as Comparative Molecular Field Analysis (4,12) (CoMFA) and Catalyst (13) has limited both the evaluation and use of other QSAR methodologies. Often well-known issues associated with CoMFA and Catalyst have come to be viewed as shortcomings that simply are accepted as working limitations in a 3D-QSAR analysis. In this section we challenge this position and present 3D- and nD-QSAR methods that are able to overcome some of the issues associated with current mainstream 3D-QSAR application products. 

Folkers, G., Merz, A., Rognan, D. CoMFA Scope and Limitations. In 3D QSAR in Drug Design. Theory, Methods and Applications, Kubinyi, H. (ed.), ESCOM Science Publishers, Leiden, 1993. 

An important feature of conventional CoMFA routine is that it assumes equal sampling and a priori equal importance of all lattice points for PLS analysis, whereas the final CoMFAresult actually emphasizes the limited areas of three-dimensional space as important... 

The pseudo-receptor concept has been applied in recent years to analyze crucial ligand-receptor interaction sites and to establish 3D-QS ARs for the prediction of biological activities of ligands. A variety of application studies have shown that the pseudo-receptor concept is a versatile tool to establish 3D-QSAR models, often better in their predictive behavior compared to results obtained from classical 3D-QSAR approaches (e.g. CoMFA). Several application studies have been published which have shown the value but also the limitations of this approach. ... 

Molecular superimposition is the most critical step in any CoMFA study and it was therefore thoroughly studied by testing several different alignments. Benazoline was chosen as the template, since it is the most active ligand and has a relatively limited conformational mobility. Its lowest minimum energy conformer, in which the inter-ring torsion angle between naphtyl and imidazoline moieties is -32.3, was selected for the different molecular overlays. 

The statistics and the isocontour maps of our preliminary CoMFA model are shown in Figure 4. It can be seen that both steric and electrostatic fields contribute to the model and, within the limits of the physicochemical domain explored, the former is prevalent. 

Not all the above-mentioned studies fulfill the necessary statistical requirements, especially proper PLS component selection by cross-validation. The crucial influence of different CoMFA options on the obtained results has been demonstrated [38,1059]. More objective alignment procedures, additional fields (e.g. a better consideration of polarizability), and more efficient variable selection procedures are needed. In addition, further research is necessary to find out which of the different CoMFA options should be selected to obtain stable and reproducible results. Theoretical and practical aspects, methodology and applications, as well as some limitations of CoMFA and related approaches have recently been reviewed in a book on 3D QSAR methods [38],... 

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