An ab initio quantum mechanics calculation that correlates with ligand orientation and DNA cleavage site selectivity in camptothecin-DNA-topoisomerase I ternary cleavage complexes.

ABSTRACT: Camptothecin (CPT), a cytotoxic natural alkaloid isolated from Camptotheca acuminata, and its derivatives represent an important class of cancer chemotherapeutic drugs that act by inhibiting topoisomerase I (top1). The mechanism of top1 inhibition by CPT has been determined by X-ray crystallography. Biochemical studies carried out both in vitro and in vivo indicated that CPT has strict DNA sequence preference for -1 T and strong preference for +1 G at the cleavage site. To understand the molecular determinants for the CPT binding orientation and DNA sequence selectivity, we present a quantum mechanics calculation where only pi-pi stacking interactions were included to shed some light on the mechanism of this sequence selectivity. This ab initio calculation can not only reproduce the experi

SUBMITTER: Xiao X 

PROVIDER: S-EPMC2526349 | biostudies-literature | 2005 Jul

REPOSITORIES: biostudies-literature