Sequence selectivity of the cleavage sites induced by topoisomerase I inhibitors: a molecular dynamics study.

ABSTRACT: Topoisomerase IB (Top1) inhibitors, such as camptothecin (CPT), stabilize the Top1-DNA cleavage complex in a DNA sequence-dependent manner. The sequence selectivity of Top1 inhibitors is important for targeting specific genomic sequences of therapeutic value. However, the molecular mechanisms underlying this selectivity remain largely unknown. We performed molecular dynamics simulations to delineate structural, dynamic and energetic features that contribute to the differential sequence selectivity of the Top1 inhibitors. We found the sequence selectivity of CPT to be highly correlated with the drug binding energies, dynamic and structural properties of the linker domain. Chemical insights, gained by per-residue binding energy analysis revealed that the non-polar interaction between CPT and

SUBMITTER: Siu FM 

PROVIDER: S-EPMC3905861 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature