Fields contour maps, CoMFA

Moreover, a final 3D-QSAR model vahdation was done using a prospective study with an external test set. The 82 compounds from the data set were used in a lead optimization project. A CoMFA model gave an (cross validated) value of 0.698 for four relevant PLS components and a conventional of 0.938 were obtained for those 82 compounds. The steric descriptors contributed 54% to the total variance, whereas the electrostatic field explained 46%. The CoMSIA model led to an (cross vahdated) value of 0.660 for five PLS components and a conventional of 0.933. The contributions for steric, electrostatic, and hydrophobic fields were 25, 44, and 31%. As a result, it was proved that the basic S4-directed substituents should be replaced against more hydrophobic building blocks to improve pharmacokinetic properties. The structural and chemical interpretation of CoMFA and CoMSIA contour maps directly pointed to those regions in the Factor Xa binding site, where steric, electronic, or hydrophobic effects play a dominant role in ligand-receptor interactions. 

CoMFA (Comparative Molecular Field Analysis) and CoMSIA (Comparative Molecular Similarity Indices Analysis) not only derive a mathematical equation but also generate a contour map (e.g., steric or electrostatic fields) that should or should not be occupied by new compounds with optimized characteristics (Fig. 34.6). 

As already discussed, the functions that are used in CoMFA studies create relatively hard fields (cf. Figure 6, Section 5). Especially the variables of the steric fields sometimes show only values close to zero (no atoms around) or at the cutoff value (inside the molecules). Correspondingly, contour maps are most often fragmented and difficult to interpret, especially if a variable selection procedure has been applied in the analysis. ... 

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... 

Further CoMFA modifications, where n x n similarity index matrices are calculated from molecular fields and these matrices are correlated with biological data by PLS analysis " " or by variable selection-regression analysis, have not been discussed here. Although they are 3D QSAR approaches, no contour maps can be derived. The same restriction applies to CoMFA studies when only the SAMPLS version of PLS analysis is used. 

Fig. 7.2 CoMFA contour maps displayed with compound IH-18 (green) and the key residues in the binding site of the PD He El. a Steric field distribution and b Electrostatic field distribution...

Most often the results of a CoMFA study are presented in graphical form, with contours for favorable and unfavorable regions of the different fields e.g. Figure 60). Difference maps were proposed as tools to analyze and identify areas of interest with respect to activity and selectivity, if two different types of biological activities are compared [1011]. 

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