Alignment procedures, CoMFA

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],... 

A. N. Jain, K. Koile, and D. Chapman,/. Med. Chem., 37,2315 (1994). Compass Predicting Biological Activities from Molecular Surface Properties. Performance Comparisons on a Steroid Benchmark. The automatic alignment procedure of Compass can also be implemented with CoMFA, giving results similar to Compass (U. Norinder, Sweden, personal communication to T. I. Oprea, 1997). 

Figure 3. Alignment of I receptor ligands 1-16, 19-40, clonidine and idazoxan, resulting from a multifit procedure and used in CoMFA.

The molecular alignment, i.e. the selection and relative orientation of a certain 3D structure out of several eonformers of each molecule, is the most important determinant in a CoMFA study. Recently, a field fit procedure [1(X)5, 1006] has been proposed to improve the alignment the objective of the field fit is to minimize the residual mean square differences between a fixed template field (consisting of... 

Ungwitayatorn et al. [240] reported the 3D-QSAR CoMFA/CoMSIA studies for a series of 30 Chromone derivatives of HIVPI. The dataset was divided into a training/test set of 30/5 compounds based on the distribution of biological activity and the variety of substitution pattern. Superposition and field fit alignment criteria were used for model development in CoMFA. The best predictive CoMFA model with steric (46%) and electrostatic (54%) fields gave cross-validated of 0.763 and non-cross-validated of 0.967 with a standard error of estimate (S) of 5.092. The PLS protocol and stepwise procedure were... 

Of course, any risks in the generation of the conformations and in the alignment could be avoided by looking at the 3D structures of ligand-protein complexes which are derived from X-ray crystallographic or multidimensional NMR studies. The advantage of such a procedure is obvious but the question arises is CoMFA really the adequate tool for such cases ... 

CoMFA is a powerful 3D QSAR method which has already shown its practical value in many cases. The results obtained depend a lot on the care that is taken in the definition of the 3D pharmacophore and in the alignment of the molecules. Soft fields seem to be better than hard fields, especially for the interpretation of the contour maps. Variable selection seems unnecessary if such fields are used. On the other hand, the new GOLPE-guided regional selection looks more promising than other variable selection procedures. A general problem is the... 

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