The Rational Discovery and Development of Disordered Protein Ligands

Abstract

Intrinsically disordered proteins play vital roles in biology and their dysfunction contributes to many major disease states, making them appealing pharmacological targets. These proteins are challenging targets for rational ligand discovery or drug design because they are highly dynamic and fluctuate through a diverse set of conformations, frustrating structure-based approaches. This dissertation describes the unique properties of disordered proteins that challenge ligand design strategies, then details methodologies designed to address these challenges. Chapter 2 details the in silico and in vitro methods used to identify and validate ligands of the disordered protein tau. Chapter 3 then further examines these compounds and how they interact with tau, as well as utilizing analogous compounds to understand the structure/function relationships that dictate their activity. Chapter 4 illustrates the adaptability of these approaches by utilizing similar methodologies to identify ligands of a different disordered protein system, phenol soluble modulins.