Join the Department of Chemistry for a seminar featuring Erik Nordquist, a current postdoc at the University of Maryland, Baltimore. Nordquist will discuss targeted protein degradation as a promising theraputic approach to address drug resistance in cancer and how computer-aided drug design can accelerate the design process.

Seminar Details

Targeted protein degradation such as Proteolysis Targeting Chimeras (PROTACs) is a promising therapeutic approach to address drug resistance in cancer. They are small molecules which link a warhead that binds a target protein to a binder of an E3 ubiquitin ligase. The goal is to stabilize the target-E3 complex, thereby causing the target to be degraded by the ubiquitin-proteasomal system (UPS) and have several key advantages including reduced susceptibility to resistance-conferring mutations. Currently, the design of PROTACs is a slow, iterative process which computer-aided drug design (CADD) can accelerate. Site Identification by Ligand Competitive Saturation (SILCS) is an atomistic molecular dynamics (MD) simulation method that generates functional group affinity maps (FragMap) for various small molecule probes that encompass the protein’s surface and interior pockets. Docking ligands into the field of the FragMaps is then used to calculate binding affinities. Furthermore, complimentary regions in FragMaps can be used to predict protein-protein interactions (PPI). We are combining these capabilities to better drive PROTAC design such as predicting the PPI complex structures and quantitatively ranking the PROTACs affinity for the interfaces. Other work in the MacKerell lab will also be briefly discussed, including developments of the Drude polarizable force field for water, divalent cations and nucleic acids.