Fig. 6. Flowchart for expedited PROTAC discovery. Improved in silico modeling of ternary complexes can predict which PROTACs will form suitable ternary complexes to induce ubiquitination. The top predicted PROTACs can then be synthesized. Next, molecules will be tested for engagement in in vitro ternary complex assays and for their ability to degrade the POI in cells. For cell active PROTACs, ternary complex structures can be solved enabling structure guided design of more potent PROTACs. This cycle can allow for iterative rounds of PROTAC design until an optimized PROTAC molecule is developed.
