Molecular Glues: New Drug Modalities

This lecture explores the concept of molecular glues as new drug modalities, focusing on PROTACS and the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. It delves into the binding driving forces, the energetics of binding, molecular interactions in biomolecules such as van der Waals interactions and hydrogen bonds, and the quantification of binding interactions. The lecture also covers drug binding by proteins, the drug development process, and the structural characterization for the ternary complex. It concludes by discussing the implications of PROTACS versus molecular glues, the energetic and structural contributions to small molecule binding, the thermodynamics of binding, experimental approaches to measure binding, and high-throughput strategies for protein degradation and drug screening.