Molecular docking approach on the Topoisomerase I inhibitors series included in the NCI anti-cancer agents mechanism database.

Topoisomerase I (Top1) is an essential enzyme participating to all those processes associated with separation of DNA strands. It manages superhelical tensions through the transient breakage of one strand of duplex DNA, followed by the unwinding of supercoiled DNA. Camptothecins, a class of alkaloids extracted from the wood of a Chinese tree, were found to be potent inhibitors of Topoisomerase I. The National Cancer Institute (NCI) Anti-cancer Agents Mechanism Database contains several camptothecins derivatives, classified as selective Top1 inhibitors. In this work we performed molecular docking studies on 24 camptothecin-like inhibitors present in this database (using Autodock 3.0.5). In order to consider the different orientations of the active site residues, docking was performed using four different structures of a Top1-DNA complex. The results obtained allowed us to analyze some conformations adopted by the inhibitors during active site binding, confirming the role of hydrogen bond and contributed to clarify the loss of activity due to single point mutations.