PROTACs designing using computational chemistry tools
The heterobifunctional molecule is proteolysis-targeting chimeras (PROTACs) having kinase ATP-competitive inhibitor connected to an E3 ubiquitin ligase recruiting ligand connected by poly(ethylene glycol) linker through an amide bond.
Upon ternary complex formation, the recruited E3ligase induces ubiquitination of the kinase and results in proteasome-dependent degradation.
The ternary complex of E3 CRBN, PTK2, and Protac was modeled with the following steps:
Identifying the aggregation sites of CRBN and kinase based on exposed hydrophobic pockets
Protein-protein docking based on the aggregation sites and
Low energy complexes and having binding site accessibility were selected.
Confirmation sampling of the PROTACs and selected low energy conformers for docking.
Docking of the low-energy conformers of PROTACs into the corresponding pockets.
The two complexes were refined to remove the steric clashes.
Molecular dynamics analysis and identifying the stable complex.
The final PROTACs binding energy will be calculated.
Identifying the linker length based on binding energy, stability, and the contact surface of in ternary complex using molecular dynamics and free energy perturbations.