A two-component approach to predicting antitumor activity from chemical structure in large-scale screening.

A new way of combining physicochemical parameters such as the octanol/water partition coefficient (or log P) with molecular structure features has been devised to predict antitumor activity on a large, diverse set of compounds. This is done by adding the log P parameter as a separate component to an earlier method based on structure. The two-component approach is motivated by the dual concepts of accessibility and specificity. Extensive testing shows improvement in performance for the two-component method over the use of structure alone. All the compounds with definitive biological results in the in vivo NCI prescreen form the training set. The method separates the training set into disjoint subsets depending on the range of log P. Therefore, structure fragments receive activity weights that vary with the log P range. This change in weights accounts for the improved performance rather than any difference in the structural characteristics of the compounds in the different log P ranges.