Structures and Machanisms of PROTAC


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Introduction

PROTACS is a bifunctional molecule that degrades disease-related target proteins by hijacking ubiquitin proteasome system (UPS). UPS and autophagy/lysosome pathways are the main pathways for intracellular protein degradation and maintenance of balance in vivo. Proteasome recognizes proteins that mark ubiquitin, a small 76-amino acid protein that is highly conserved in all eukaryotes. Protein ubiquitin is an ATP-dependent enzymatic reaction, which includes three enzymes: ubiquitin activating enzyme (E1 enzyme), ubiquitin coupling enzyme (E2 enzyme) and ubiquitin ligase (E3 enzyme). First, ubiquitin molecules are activated by E1 enzyme in a ATP-dependent manner. Then, the activated ubiquitin is transferred to the E2 enzyme, and finally, the E3 ligase catalyzes the transfer of the ubiquitin molecule from E2 to the lysine residue on the substrate by forming a covalent bond. Appropriate ubiquitin-labeled proteins can be recognized by 26S proteasome and destroyed by proteolysis.

Mode of action

The mode of action of PROTAC is greatly changing the mode of "available drug" targets. The pharmacogenicity of the target protein usually depends on the design of small molecules that can bind to the cavity or pocket to inhibit its activity, resulting in therapeutic benefits. So far, thousands of protein-protein interactions (PPI) are known, without deep pockets, lack of clear binding sites and flat protein interfaces, so they are still challenging targets for small molecules. On the other hand, PROTAC has been proved to be suitable for targeting transcription factors or membrane-binding proteins that lack active binding sites. With regard to their mode of action, in the case of PROTAC, it is event-driven, not occupancy-driven. The space-occupying driving mode is a sign of classical receptor pharmacology, which requires a higher drug concentration to maintain a targeted space-occupying level that provides sufficient clinical benefits. However, the higher drug concentration is also related to the non-target effect, and the drugs with high specificity and good pharmacokinetic characteristics can reduce the non-target effect. On the contrary, PROTAC showed catalytic behavior in inducing proteasome degradation at the substoichiometric level. Their efficacy is not limited by equilibrium share.

Our Services

BOC Sciences will devote itself to the analysis of small molecular structure in order to finally complete the discovery and design of PROTAC molecules. With senior high-level scientists and experienced chemical structure optimization platform, we are fully competent and committed to providing our customers with high quality and reliable PROTAC. We can also help customers with protein-ligand structural analysis. For more detailed information, please feel free to contact us.

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