MODELING TOPOISOMERASE-DNA INTERACTIONS AND DESIGN of TRAPPING INHIBITORS USED FOR CANCER
by
___________________
Copyright © Soaring Bear 1998
all rights reserved
A Dissertation Submitted to the Faculty of the
DEPARTMENT OF PHARMACEUTICAL SCIENCES
In Partial Fulfillment of the Requirements
For the Degree of PhD
With a Major in Pharmaceutical Sciences
and a Minor in Biochemistry
In the Graduate College
The University of Arizona, 1998
ABSTRACT
INTRODUCTION
Cancer touches all of us Topoisomerase targeting of chemotherapy Three types of topoisomerase in humans Oncogenes near topoisomerase genes help targeting Targeting high levels of topoisomerase 2 How inhibition of topoisomerase 2 kills cells Inhibition of topoisomerase Designing better topoisomerase trapping agents Intercalation is insufficient Trans-esterification Kinetics of topoisomerase winding of DNA Categorizing topoisomerase inhibitors Amonafide & Azonafide background STRUCTURE RESULTS AND DISCUSSION
Sequence analysis of human topoisomerase Yeast structure insights Overhang 5 or 3? Drug selected mutant bioinformatic analysis Homology of human topoisomerase structure from yeast Active Site Analysis INHIBITOR RESULTS AND DISCUSSION
Error in force field based calculations SAR of topoisomerase inhibitors Conclusions, implications and suggestion for future study
Topoisomerase inhibiting chemotherapy is most appropriate in cancers containing high levels of topoisomerase. Study of these drugs is particularly difficult because two receptors, enzyme plus DNA, are involved. Genes of all three known human topoisomerases have neighboring oncogenes and those amplified receptors may be used to target topoisomerase inhibitors to transformed cells. To facilitate design of inhibitors, modeling tools of graphic imaging, sequence analysis, homology, molecular dynamics, energy evaluation, and QSAR were used. The principle findings are: