An Ab Initio Quantum Mechanics Calculation that Correlates with Ligand Orientation and DNA Cleavage Site Selectivity in Camptothecin-DNA-Topoisomerase I Ternary Cleavage Complexes

摘要

The discovery of the cytotoxic agent camptothecin (CPT,1) (Chart 1) from the Chinese tree Camptotheca acuminata not only has provided a lead for the development of new anticancer drugs but also has led to the validation of topoisomerase I (top1) as a chemotherapeutic target.Top1 is a nuclear enzyme responsible for solving the topological problems associated with DNA replication and transcription by nicking and resealing one strand of DNA in a DNA duplex.These processes are achieved by a reversible transesterification reaction between Tyr723 of top1 and the phos-phodiester bond of the DNA.The X-ray crystal structure of the ternary complex consisting of DNA,top1,and topotecan (TPT,2),a therapeutically useful analogue of CPT,shows that the pentacyclic ring system of CPT intercalates into the DNA base pair step at the cleavage site,resulting in increased physical distance between the cleaved DNA termini and,consequently,inhibition of the religation step catalyzed by top1.Interestingly,none of the three previously proposed binding models of CPT at the cleavage site are consistent with the X-ray crystal structure.