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.