Computational Modeling of First-In-Class G9a/GLP Protein by Using PROTAC Degrader

G9a leads to unusual chromatin structure and gene suppression, disrupting proper cellular functions and contributing to the development of detrimental diseases like cancer—more specifically, colorectal, lung, and head and neck cancer.  PROTAC is a technology that attaches to the target protein (G9a in this work) while also attaching to the E3 ubiquitin ligase; the PROTAC role in this is to transmit the ubiquitin molecules to the G9a protein, aiding in the degradation of the target protein. We hypothesize that chemical modulation in the PROTAC structure can help design more potent PROTACs binding G9a protein. P2Rank helped design the prediction of ligand binding sites with the proteins. P2Rank integrates machine learning algorithms and systematic information to help identify the potential binding areas on the protein’s surface. For docking, HADDOCK is used, a flexible software aiding in the modeling of biomolecular complexes. HADDOCK prioritizes experimental data supporting the docking process to embody different information to refine complex structures. Current research will help develop PROTACs that can degrade the G9a protein formed in various cancer cells.