During the last 10 years, my research focus has centered on the discovery and development of novel small molecules to target neurodegenerative diseases, including Pontocerebellar Hypoplasia Type 1B, Batten disease, Alzheimer’s disease, and ALS. I am interested in understanding protein-protein and protein-RNA interactions and, particularly in developing compounds to address issues that arise when mutations, post-translational modifications, or splice variants deleteriously affect these interactions. My lab discovered a small molecule that disrupted RNA binding to the RNA exosome and mimicked Pontocerebellar Hypoplasia Type 1B – like nervous system defects in zebrafish (ACS Chem Biol. 2018 Oct 19;13(10):3000-3010). More recently – and relevant to this talk – my lab was the first to discover small molecule effectors of TDP-43 – finding two novel compounds that bound specifically to folded domains of TDP-43 and were effective in reducing motor deficits in a Drosophila model of ALS (ACS Chem Biol. 2019 Sep 20;14(9):2006-2013, ACS Chem Biol. 2020 Nov 20;15(11):2854-2859). Discovery of these compounds allowed us to define unique structural elements of TDP-43 that I will discuss during my talk. The focus of my talk will be on how we have used structural biology (through in silico docking) to discover new molecules and how the molecules have helped in discovering new structural elements. Our research endeavors have led to advancements in understanding and addressing neurodegenerative diseases through small molecule interventions by targeting protein-RNA interactions that have led to the discovery of unique structural interplay.