A novel approach for the virtual screening and rational design of anticancer compounds

A topological substructural approach to molecular design (TOSS-MODE) has be en introduced for the selection and design of anticancer compounds. A quant itative model that discriminates anticancer compounds from the inactive one s in a training series was obtained. This model permits the correct classif ication of 91.43% of compounds in an external prediction set with only 1.43 % of false actives and 7.14% of false inactives. The model developed is the n used in a simulation of a virtual search for Ras FTase inhibitors; 87% of the Ras FTase inhibitors used in this simulated search were correctly clas sified, thus indicating the ability of the TOSS-MODE model of finding lead compounds with novel structures and mechanism of action. Finally, a series of carbonucleosides was designed, and the compounds were classified as acti ve/inactive anticancer compounds by using the model developed here. From th e compounds so-designed, 20 were synthesized and evaluated experimentally f or their antitumor effects on the proliferation of murine leukemia cells (L 1210/0) and human T-lymphocyte cells (Molt4/C8 and CEM/0); 80% of these com pounds were well-classified, as active or inactive, and only two pairs of i someric compounds were false actives. The chloropurine derivatives were the most active compounds, especially compounds 6c,d.