Date Approved


Embargo Period


Document Type


Degree Name

M.S. Pharmaceutical Sciences


Chemistry and Biochemistry


College of Science & Mathematics


Wu, Chun

Committee Member 1

Caputo, Gregory

Committee Member 2

Keck, Thomas


cancer, DNA, G-quadruplex, MMPBSA, molecular dynamics simulation, molecular modeling


Drugs--Design; Computer simulation


Medicinal and Pharmaceutical Chemistry | Pharmacy and Pharmaceutical Sciences


Free ligand binding molecular dynamic simulations are a powerful tool used to probe the ligand binding process, mechanism and pathway and the insight gained can help expedite the early stages of drug discovery. Using these methods, we model the binding of two small molecule anti-cancer agents BRACO19 and CX-5461 to a variety of DNA G-quadruplexes (G4s) and a DNA Duplex. The first study focuses on the binding of BRACO19 to three different topological folds (parallel, anti-parallel and hybrid) of the human telomeric G4s. Our detailed analysis identified the most stable binding modes were end stacking and groove binding for the G4s and duplex, respectively. With the parallel scaffold being most favorable, we suggest a conformation-selection mechanism where the relative population of the three scaffolds shifts to an increase of the parallel scaffold upon BRACO19 binding. The second study focuses on the binding of CX-5461 to human telomeric, c-KIT1, and c-Myc G4s. Our analysis was able to provide insight into a FRET-melting temperature increase assay measured the stabilizing effects of CX-5461 to each of these targets. The energetic and structural differences explained the different melting temperature between the G4s, while CX-5461's lack of intercalation to the duplex explained the difference between the G4s and duplex. Using our insight CX-5461 derivatives were deigned and docked with higher selectivity to the G4s over the duplex, which might aid in further optimization of CX-5461.