Interpretation of CoMFA results - A probe set study using hydrophobic fields

The main-purpose of the study was to examine the correctness of interpretat ion of CoMFA results using an artificially designed data set with predefine d contributions of the compound substituents to activity. The activity valu es were assigned according to additive (sum of substituent pi-constants);an d nonlinear (sum of absolute values of substituent pi-constants) dependenci es on hydrophobicity. Predictions by 3D (HINT hydrophobic fields) and logP (HINT and CLOGP values) presentations of hydrophobicity were compared and s imilarity between standard CoMFA and hydrophobic fields was evaluated. The main results are: (i) the cross- validated R-2 (Q(2)) values with the first PLS components of the field models may be indicative for identification of the underlying property(ies) in the data set providing each field alone yi elds a satisfactory predictive model with several components; (ii) the logP values alone are not predictive when the target property is nonlinearly de pendent on the explanatory property; (iii) similarity between fields of dif ferent nature (steric, electrostatic, hydrophobic) can be evaluated by cros s- and non-cross-validation correlations between the X-scores of the first components - low Q(2) and R-2 suggest that the most informative variances o f the compared fields are different; (iv) the CoMFA graphical display is ve ry much dependent on the distribution of the positive and negative field te rms if their contributions to the whole field signal are not symmetrically distributed the default CoMFA contour view setting can lead to wrong displa ys and, consequently, wrong interpretation of the results.