Molecular Dynamics Simulations of Molecular Glue Degraders: targeting the DDB1-CDK12-Cyclin K complex for Selective Protein Degradation

Identifier:  TFG:9034

Handle: https://hdl.handle.net/20.500.11797/TFG9034

Authors:  Jornet Margalef, Ferran

Abstract:
Targeted protein degradation using molecular glue degraders is a novel therapeutic strategy for modulating hard-to-drug proteins like CDK12. This thesis explores whether molecular dynamics simulations can clarify the structural and energetic basis of the DDB1–CDK12–Cyclin K complex formation mediated by various ligands. Eight systems were simulated for 1 microsecond each. The simulations revealed key residue interactions and maintained complex stability. While strong binding affinity often aligned with complex formation, it did not directly predict Cyclin K degradation efficiency. SR-4835 and LL-K12-18 emerged as the most promising ligands due to favorable binding profiles and validated in vitro activity.