| Description |
This dissertation research focuses on exploiting computational modeling and biochemical experiments to understand glycosaminoglycan (GAG) biosynthesis, elucidate GAG-protein interactions and discover small molecule drugs to treat a rare disease, NGLY1 deficiency, which is associated with defective deglycosylation of N-glycoproteins. Glycans play important roles in the regulation of many biological and pathological processes, such as anticoagulation, angiogenesis, and cell proliferation/differentiation. Herein, both computational and biochemical approaches were applied to study three projects in glycobiology. The first project is titled "Predicting Heparin/Heparan Sulfate Biosynthetic Pathway in the Generation of Antithrombin Binding Motif using Combinatorial Virtual Library Screening." Computational modeling was utilized to understand how different heparan sulfate (HS) biosynthetic enzymes evolve and coordinate together to generate antithrombin binding domain. Further biochemical experiments are ongoing to assess the computational predictions. Based on the knowledge of GAG-protein interactions gained on the above research, another project was designed to find small molecule regulators targeting GAG biosynthetic enzymes. This second project focuses on "Discovery of Novel Xylosides to Regulate GAG Biosynthesis." Several novel xylosides are found to have better GAG chain priming activity than previously reported synthetic scaffolds. Computational modeling further rationalized the xyloside priming activities. The iv motivation of developing small molecule drugs in glycobiology field drives the next research that targets glycan deglycosylation associated human diseases with a special interest in N-Glycanase deficiency. This third project is titled "Developing Small Molecule Inhibitors of endo-β-N-acetylglucosaminidase (ENGASE) as a Novel Treatment for a Rare Genetic Disease, N-glycanase (NGLY1) Deficiency." Structure-based virtual screening was conducted, and the first small molecule lead compounds were successfully developed, targeting ENGase for the potential treatment of NGLY1 deficiency. Subsequent efforts are directed to optimize the lead compound structure and discover novel scaffolds as well. In summary, this work combined computational and biochemical efforts to study the GAG biosynthesis and also pave the way for translational drug discovery efforts in glycoscience. |
