Research on Bioinformatics and Molecular Simulation in Proteolysis Targeting Chimeras (PROTAC)
Keywords:
Proteolysis targeting chimera, E3 ubiquitin ligase, Target landscape, Ternary complex computational simulation, Protein translational modification, Heterobifunctional moleculeAbstract
Proteolysis targeting chimera (PROTAC) is a drug discovery strategy using a ubiquitin-proteasome system (UPS) to degrade the target protein. Unlike traditional small molecule drugs utilizing occupancy-driven pharmacology as the mode of action (MOA) to regulate protein activity, PROTACs function through forming stable target protein-PROTAC-E3 ubiquitin ligase ternary complex and use the ubiquitin-proteasome system to degrade the target protein. However, only a few E3 ubiquitin ligases have been used in PROTAC drug design now, and the space of target proteins that PROTAC can target needs to be further expanded. On the other hand, the complicated system of ternary crystal structures is difficult to capture and identify, computational simulation provides modeling of PROTAC-mediated ternary complex formation with effective approaches. Because of this, this review describes the recent progress of bioinformatics in expanding the landscape of E3 ubiquitin ligases and target proteins and summarizes the methods of computation simulation in modeling PROTAC ternary complex. Finally, the trend of development about PROTAC is prospected.
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