DegraderTCM: A Computationally Sparing Approach for Predicting Ternary Degradation Complexes

Proteolysis
targeting
chimeras (PROTACs or degraders) represent
a novel therapeutic modality that has raised interest thanks to promising
results and currently undergoing clinical testing. PROTACs induce
the selective proteasomal degradation of undesired proteins by the
formation of ternary complexes (TCs). Having knowledge of the 3D structure
of TCs is crucial for the design of PROTAC drugs. Here, we describe
DegraderTCM, a new computational method for modeling PROTAC-mediated
TCs that requires low computational power and provides sound results
in a short time span. We validated DegraderTCM against a selected
set of experimentally determined structures and defined a method to
predict the PROTAC degradation activity based on the computed TC structure.
Finally, we modeled TCs of known degraders holding significance for
defining the method’s applicability domain. A retrospective
analysis of structure–activity relationships unveiled possibilities
for utilizing DegraderTCM in the initial stages of designing novel
PROTAC drugs.