Conception in silico de nouveaux inhibiteurs de la topoisomérase I de cellules cancéreuses.

Abstract

Human DNA Topoisomérase I (topo I) is the tar get of several drugs commonly used in cancer chemotherapy. These drugs induce topo-DNA co mplexes that eventually trigger cell death. Several flavonoides have been shown as inhib itors of topo I, having an anticancer activity. Using the methods of molecular modeling in pa rticularl the docking by the Surflex program, we theoretically evaluated the affinity of four fla vonoids: myricetin, fisetin, quercetin and apigenin, presented in recent studies as inhibitors of topo I. Myricetin with the lowest IC 50 (11.1 ± 2.0 μ M) gave the best affinity (7.01 M -1 ). For the development in silico of novel molecules most powerful myricetin, we have made sev eral substitutions. Replacing the hydroxyl group carried by the carbone C3 ́ of the myricetin b y an alcoholic group CH 2 OH significantly improves the affinity increases from 7.01 M -1 to 8.79 M -1 . The application of the rule of Lipinski inform s in a positive way about the ADME properties of this new molecule that is as an inhibitor potent ially more active than myricetin.