ENHANCING THE FLEXIBILITY AND ADAPTABILITY OF THE DARC STRUCTURAL REPRESENTATION FOR COMPUTER-AIDED DRUG DESIGN

Noticeable progress has been achieved in the determination of dynamic topochromatic variables for the structural representation of compounds and their situation in a given population. These independent structur al variables can be further combined into more complex variables. Thei r contributions to the evolution of an associated property can therefo re be evaluated with certainty. The risk of having correlated variable s is avoided while the structural description remains exhaustive. In o rder to enhance the interpretative ability of the QSAR model, one or s everal physicochemical properties can be taken with these structural p arameters as explanatory variables. Typically, partition coefficients, 3-D and quantum mechanical data are used for this purpose. The struct ural aspects not taken into account by the physicochemical parameters are reflected in the remaining topochromatic variables. The use of the se new concepts is presented in a study of carbazole mutagenicity. The model explains 99% of the total variance with one external property a nd four additional topochromatic variables. The modulation of the heal of formation of an intermediate by two topochromatic variables sugges ts a much more precise interpretation than a simple combination of the usual external variables.