A novel approach for the virtual screening and rational design of anticancer compounds.
A topological substructural approach to molecular design (TOSS-MODE) has been introduced for the selection and design of anticancer compounds. A quantitative model that discriminates anticancer compounds from the inactive ones in a training series was obtained. This model permits the correct classification 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 then 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 classified, 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 active/inactive anticancer compounds by using the model developed here. From the compounds so-designed, 20 were synthesized and evaluated experimentally for their antitumor effects on the proliferation of murine leukemia cells (L1210/0) and human T-lymphocyte cells (Molt4/C8 and CEM/0); 80% of these compounds were well-classified, as active or inactive, and only two pairs of isomeric compounds were false actives. The chloropurine derivatives were the most active compounds, especially compounds 6c, d.
Estrada
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E
Faculty of Pharmacy, Department of Organic Chemistry, Universidad de Santiago de Compostela, 15706 Santiago de Compostela, Spain. estrada66@yahoo.com
Uriarte
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E
Montero
A
A
Teijeira
M
M
Santana
L
L
De Clercq
E
E
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000145:classification / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016208:Databases, Factual; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology; D012984:Software; D013601:T-Lymphocytes; D014407:Tumor Cells, Cultured
C409869:6-chloro-9-(2-(hydroxymethyl)cyclopentylmethyl)-9H-purine; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011687:Purines; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase