PROTAC Modeling

Targeted Protein Degradation (TPD) is an approach that is attracting substantial interest for modulating challenging drug targets. A major class of TPDs are Proteolysis-Targeting Chimera protein degraders (PROTACs). PROTACs are heterobifunctional molecules where two ligands are joined by linker. One ligand recruits the target and the other recruits and binds an E3 ubiquitin ligase. This interaction induces ubiquitylation of the target and degradation by the ubiquitin-proteasome system, the PROTAC is then recycled.
The MolSoft ICM PROTAC modeling method:

Start with structures of target protein and cereblon or VHL complexes with their respective binding ligands/moieties
PROTAC molecule is modeled into first complex and then into second complex using ligands as templates
Internal coordinate MC simulation sampling linker torsions optimizes tripartite complex
Surrounding sidechains also flexible
Resulting ensemble of low energy conformers is re-evaluated using scoring function optimized for protein-protein docking

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