Structure-guided and fragment-based drug design has matured over the past decades, and numerous successful examples have demonstrated our ability to design and optimize small molecule inhibitors of kinases, proteases and other “classic targets”. Tomorrow’s targets, however, will be different, and may include proteins without defined structure, to which our current technologies are not applicable. These intrinsically disordered proteins (IDPs) are often key regulatory proteins, and their dysregulation or aggregation may lead to disease. More recent studies have shown that some IDPs can undergo lipid-lipid phase separation (LLPS) to form membraneless organelles which can be highly functional but otherwise remain poorly characterized.
Given our inability to apply current structure-guided drug design methods to IDPs, the postdoc project aims at identifying novel ways of targeting IDPs, either in aqueous phase or as membraneless organelles. Various biophysical techniques such as NMR spectroscopy, surface plasmon resonance, second harmonic generation, and mass spectroscopy as well as microscopic and cellular technologies are available to explore new avenues to target intrinsically disordered proteins to facilitate drug discovery for tomorrow’s targets.