2017 Theses Doctoral
Molecular Design as a Tool to Understand and Manipulate Cell Death
Phenotypic screening is a powerful technique for discovering small organic molecules with the ability to effect a desired change in biological systems. Yet, because of the diversity of ways that a small molecule can alter a biological system, phenotypic screens provide little to no insight into how a hit molecule elicits such a change. Understanding a molecule’s mechanism of action—which proteins it engages, where it localizes, and its reactivity—is critical to fully developing a hit molecule into a research tool or a therapeutic. In this dissertation, strategic, hypothesis-driven molecular design is used as a cornerstone technique to understand the mechanism of action of molecules that regulate cell death. In the first part, we examine the structural requirements for ferroptotic death induction by the 1,2-dioxolane FINO2. Next, we create a panel of ferroptosis inhibiting molecules that are targeted to specific organelles and used as imaging agents in order to examine the contribution of different organelles to ferroptosis. I then apply molecular design in a target-based context to discover which molecular features of LOC14 promote association with its receptor protein. Finally, I discuss a computational approach to developing a ligand that inhibits protein-protein interactions mediated by the small GTPase Rheb.
Subjects
Files
- Gaschler_columbia_0054D_14114.pdf application/pdf 28.8 MB Download File
More About This Work
- Academic Units
- Chemistry
- Thesis Advisors
- Stockwell, Brent
- Degree
- Ph.D., Columbia University
- Published Here
- August 25, 2017