Date Approved


Embargo Period


Document Type


Degree Name

M.S. Bioinformatics


Chemistry and Biochemistry


College of Science & Mathematics


Wu, Chun

Committee Member 1

Jonnalagadda, Subash C.

Committee Member 2

Hickman, Mark J.


Cancer Research, Computational Drug Design, G-quadruplex DNA, Molecular Dynamics Simulations, Molecular Modeling, Topoisomerase I


Drugs--Design; Cancer--Research; Bioinformatics


Bioinformatics | Pharmaceutics and Drug Design


Computational methods are becoming essential in drug discovery as they provide information that traditional drug development methods lack. Using these methods to understand drug-receptor interactions in detail, researchers are able to efficiently design promising drug candidates. In this study, extra precision Glide docking, molecular dynamics simulations and MMGBSA binding energy calculations provided information about the binding behavior of small molecules to two specific targets for current cancer therapeutics: G-quadruplex DNA and Topoisomerase I enzyme. The first study focuses on the compound Telomestatin, which induces apoptosis of various cancer cells with a relatively low effect on somatic cells due to its high selectivity toward G-quadruplex over duplex DNA. Three major binding poses were discovered: top end stacking, bottom end stacking and a groove binding. A high resolution structure of this complex does not yet exist, so this is the first time Telomestatin binding modes have been reported. The second study focuses on 8 Camptothecin class Topoisomerase I inhibitors, which have been reported to effectively treat multiple types of cancer, however are limited by their drug resistance. Recent computational studies have indicated that the mutations near the active binding site of the drug can significantly weaken the drug binding and may be a major cause of the drug resistance. Here, a complete study of each Camptothecin analog in each mutated complex in the active binding site is presented. On this set of mutant complexes, Topotecan and Camptothecin have much smaller binding energy decrease than a set of new Camptopthcin derivatives (Lurtotecan, LESN-38, Gimatecan, Exatecan and Belotecan) currently under clinical trials. Lucanthone, a non-Camptothecin, shows comparable results to Topotecan and Camptothecin, indicating that it may exhibit the least drug resistance and is therefore a promising candidate for future studies as a Topoisomerase I inhibitor. In addition, a trend is observed from our binding energy data that the shorter the distance of a mutant to a ligand, the greater the decrease in binding energy (with one exception). The results found in each of these binding studies will be utilized to further advance effective cancer therapeutics in the future.