Doctor of Philosophy, The Ohio State University, 2024, Chemistry

Molecular docking and molecular dynamics simulations are two commonly used computational techniques for the in silico evaluation of receptor-ligand binding and characterization of biomacromolecules. This work presents two independent projects to elucidate the molecular interactions in different prospective protein targets and provide physical insights into structure-based drug design. The focus of the first part is the “interacts-with-Spt6” protein (IWS1), a eukaryotic transcription elongation factor present in the RNAP II polymerase (RNAP II) complexes. IWS1 is gaining increasing attention as recent works revealed its collaborative actions with many formerly identified transcription factors of known regulatory effects and its direct interaction with the catalytic alpha subunit of RNAP II (RPB1). However, having about 70% of residues in human IWS1 being intrinsically disordered, its structure and function are not fully understood. Motivated by the recently discovered connection between IWS1 and liposarcoma (LPS), a cancer that can grow and spread aggressively, we initiated the effort of finding drug molecules targeting IWS1 to suppress transcriptional activities in cancer cells. To begin with, we analyzed the supermolecular arrangement, the protein interactions within the structured core, and the potential interactions with chromatin in the intrinsically disordered region of hIWS1 based on various recent studies of the structures and biological functions of IWS1. We then identified a potential binding pocket on IWS1's interface with Spt6 for a drug molecule to act as a competitive inhibitor that downregulates the transcriptional activity of RNAP II by diminishing the association of IWS1/Spt6. Next, we designed and performed a series of molecular docking calculations. Among the top-ranked compounds from the virtual screening of FDA-approved drugs, Ketotifen and Desloratadine were selected for experimental validation and were shown to reduce the association of IWS (open full item for complete abstract)

Committee: Christopher Hadad (Advisor); Rafael Bruschweiler (Committee Member); Alexander Sokolov (Committee Member) Subjects: Chemistry