Small molecules inducing protein degradation are important pharmacological tools to interrogate complex biology and are rapidly translating into clinical agents. Selectivity remains a limiting challenge in the design of CRL4 CRBN recruiting PROTACs.
Bouguenina et al. used structural insights from known CRL4 CRBN neo-substrates, degron blocking design principles, and computational modeling to predict key interactions mediating the formation of productive ternary complexes.
The design principles on a previously published BRD9 PROTAC and generated an analogue with an improved selectivity profile. The computational modelling pipeline shows that the degron blocking design does not impact PROTAC induced ternary complex formation.
The computational modeling process was used to predict key interactions mediating the formation of productive ternary complexes. Molecular dynamics simulations were used to study the binding of the PROTACs to the target proteins and to predict the stability of the ternary complex. The application of free energy calculations estimated the binding affinity of the PROTACs to the target proteins. The design principles were applied on a previously published BRD9 PROTAC and generated an analogue with an improved selectivity profile, which was validated experimentally.