PROTAC

From Proteopedia

Representative PROTAC from PROTACpedia targeting EGFR Epidermal growth factor receptor P00533. target binding ligandlinkerE3 binder

A Proteolysis-Targeting Chimera (PROTAC) is a small protein with two active domains joined by a linker. PROTACs represent an alternative to conventional enzyme inhibitors, by enabling proteasome induced degradation of the target protein ^[1].

PROTACpedia

PROTACpedia ^[2] is a collaborative and comprehensive, high-quality and freely accessible resource of manually curated data on Proteolysis Targeting Chimeras (PROTACs). Users can search PROTACpedia by various parameters such as Target name, UniProt ID, SMILES substructure or by details regarding a publication or patent.

The statistics page of PROTACpedia allows to overview current distribution on PROTACs of IC₅₀, DC₅₀, linker, etc.

Predicting PROTAC-induced ternary complexes

PRosettaC ^[3] is a computational resource for the prediction of PROTAC-induced ternary complexes ^[4]. PRosettaC receives as input, two protein structures (protein target and E3 ligase), including their appropriate ligands (binders), as well as the PROTAC chemical structure in a SMILES representation, and outputs predicted models for the ternary complex. Other methods become available ^[5][6].

References

1. ↑ Gadd MS, Testa A, Lucas X, Chan KH, Chen W, Lamont DJ, Zengerle M, Ciulli A. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat Chem Biol. 2017 Mar 13. doi: 10.1038/nchembio.2329. PMID:28288108 doi:http://dx.doi.org/10.1038/nchembio.2329
2. ↑ PROTACpedia https://protacpedia.weizmann.ac.il/, a resource of manually curated data on Proteolysis Targeting Chimeras (PROTACs).
3. ↑ PRosettaC https://prosettac.weizmann.ac.il, a computational resource for the prediction of PROTAC-induced ternary complexes.
4. ↑ Zaidman D, Prilusky J, London N. PRosettaC: Rosetta based modeling of PROTAC mediated ternary complexes. J Chem Inf Model. 2020 Sep 25. doi: 10.1021/acs.jcim.0c00589. PMID:32976709 doi:http://dx.doi.org/10.1021/acs.jcim.0c00589
5. ↑ Drummond ML, Henry A, Li H, Williams CI. Improved Accuracy for Modeling PROTAC-Mediated Ternary Complex Formation and Targeted Protein Degradation via New In Silico Methodologies. J Chem Inf Model. 2020 Oct 26;60(10):5234-5254. doi: 10.1021/acs.jcim.0c00897., Epub 2020 Oct 12. PMID:32969649 doi:http://dx.doi.org/10.1021/acs.jcim.0c00897
6. ↑ Bai N, Miller SA, Andrianov GV, Yates M, Kirubakaran P, Karanicolas J. Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta. J Chem Inf Model. 2021 Feb 24. doi: 10.1021/acs.jcim.0c01451. PMID:33625214 doi:http://dx.doi.org/10.1021/acs.jcim.0c01451