Electronic Theses and Dissertations

Date of Award


Document Type


Degree Name

Ph.D. in Pharmaceutical Sciences

First Advisor

David Colby

Second Advisor

Robert Doerksen

Third Advisor

Jing Li


University of Mississippi

Relational Format



The use of molecular modeling in pharmaceutical research is continuously growing. This growth is a result of the increasing number of experimental structures, the development of sophisticated modeling methods, and the improvement in computer performance by using GPUs and cloud computing. Nowadays, molecular modeling is routinely used in drug discovery to investigate biological processes and molecular properties. Herein, we use molecular modeling to investigate the behaviors of compounds with unique scaffolds.

Baclofen is the only marketed GABAB receptor agonist that is used for spasticity disorders, and it has shown promise as an anti-abuse agent. However, it has disadvantages that raise the need for developing new scaffolds for the treatment of drug addiction. We used structure-based drug design to identify and design novel compounds as potential GABAB receptor agonists. For part one, virtual screening of a commercial library, pharmacophore modeling, induced-fit docking, molecular dynamics simulations, and free energy calculations were utilized. Four hits were the best-performing candidates. Part two is based on the novel class of difluoromethyl ketones that was developed by the Colby lab as GABAB receptor agonists. We proposed novel synthetically feasible β-amino difluoromethyl ketones from commercially available starting materials. Induced-fit docking was performed for these compounds, and seven displayed the optimal binding behaviors.

Flavonoids are natural products that are often observed as β-O-glycosides. They have numerous biological activities but are deglycosylated in the body. This hydrolytic lability leads to poor bioavailabilities, diminishing their biological activities and limiting their use in drug development. Deglycosylation is a common limitation for research involving O-glycosides, and one solution is the use of the difluoromethylene (-CF2-) group in the glycosidic linkage since it’s a non-hydrolyzable mimic of the oxygen atom. Although the stability of flavonoid-CF2-glycosides is expected to improve compared to flavonoid-O-glycosides, they may have different conformational properties. We investigated the conformational behavior of flavonoid-O-glycosides and flavonoid-CF2-glycosides by using molecular dynamics simulations. Compared to flavonoid-O-glycosides, flavonoid-3-CF2 glycosides and flavonoid-5-CF2-glycosides were more conformationally restricted, and flavonoid-7 CF2-glycosides had more flexibility. Our findings indicate that the conformational behavior of these molecules is dependent on the glycosylation site and the substitution pattern on the flavonoid.


Medicinal Chemistry

Available for download on Friday, February 07, 2025