Integrative Modeling of PROTAC-Mediated Ternary Complexes

Proteolysis-targeting chimeras (PROTACs),
which selectively induce
targeted protein degradation, represent an emerging drug discovery
technology. Although numerous PROTACs have been reported, designing
potent PROTACs still remains a great challenge, to some extent, due
to insufficient structural data of Target-PROTAC-E3 ternary complexes.
In this work, PROTAC-Model, an integrative computational method by
combining the FRODOCK-based protocol and RosettaDock-based refinement,
was developed to predict PROTAC-mediated ternary complex structures
and tested on 14 cases. The quality of the models was evaluated using
the criteria of the critical assessment of predicted interactions
(CAPRI). Using the unbound structures, the FRODOCK-based protocol
can generate the ternary complex structures with medium or high quality
for 8 cases out of 14. With the refinement by RosettaDock, the cases
with medium or high quality increase to 12. Compared with PRosettaC
and the method developed by Drummond et al., PROTAC-Model shows better
performance. In summary, PROTAC-Model should be useful for the rational
design of PROTACs.