Targeting intrinsically disordered proteins and biomolecular condensates with small molecule drugs [EXTRAORDINARY Nodes Seminar]

Intrinsically disordered proteins (IDPs), which represent ~40% of the human proteome, play crucial roles in a variety of biological pathways and biomolecular assemblies and have been implicated in many human diseases. IDPs do not fold into a well-defined three-dimensional structure under physiological conditions. Instead, they populate a dynamic conformational ensemble of rapidly interconverting structures. As a result, IDPs are extremely difficult to experimentally characterize and are largely considered “undruggable” by conventional structure-based drug design methods.  Our laboratory utilizes a combination of computational and biophysical methods to characterize the molecular recognition mechanisms of intrinsically disordered proteins in atomic detail.  Here I will discuss recent progress in our efforts to characterize the interactions of IDPs with small molecule drugs, understand molecular mechanisms that drive the formation of biomolecular condensate, and understand how small molecule drugs modulate biomolecular condensate stability.