What are PROTACs?

Proteolysis-targeting chimeras (PROTACs) which induce targeted protein degradation by the ubiquitin-proteasome system represent a new therapeutic strategy. Unlike traditional small-molecule strategies, which exert its efficacy mainly through binding site occupancy, PROTACs target the specific protein for degradation, thus also eliminating other functions of the protein. In additions, while some small molecules are restricted to bind to the catalytic pocket, PROTACs are capable of utilizing all surface binding pockets on the targeted protein for degradation.

PROTACs are heterobifunctional molecules, typically containing a small molecule which targets the protein of interest (warhead), a small molecule capable of recruiting an E3 ligase (E3 ligand), and a linker to conjugate the above two moieties (Figure 1).

Figure 1. The BRD4-PROTAC-VHL complex. The cyan, white and orange moieties represent the warhead, linker and E3 ligand, respectively.


PROTAC-DB is a public, web-accessible database. The chemical structures, biological activities, physiochemical properties of these compounds are manually extracted from the literature or calculated by some programs. Here, the biological activities of PROTACs contain the degradation capacity, binding affinities and cellular activities. The detailed information is as follows.

  • Degradation capacity: In general, DC50 (concentration that resulted in a 50% targeted protein degradation) and Dmax (maximal levels of protein degradation) are utilized to quantify the power of targeted protein degradation of PROTACs.However, since a large number of PROTACs lacked the above data, the percent degradation was integrated to the database, if it was assessed at least with two concentrations and each concentration was measured with at least two independent experiments. Further, the Western blotting (WB) figures were also collected by us to show the degradation capacities of PROTACs. But the WB figures are only displayed on the detailed information pages of PROTACs, not on its list pages.

  • Binding affinities: The binding affinities between PROTACs and targeted proteins, PROTACs and E3 ligases, the formation of ternary complexes are collected into PROTAC-DB. The binding affinities of the formation of ternary complexes are employed to assess the capacity of PROTAC-induced complex formation with E3 ligase and targeted protein. It can be determined through some assays between E3 ligase (targeted protein) and the complex of PROTAC and targeted protein (E3 ligase). There are four types of values, including Kd, Ki, IC50 and EC50. Only Kd and IC50 will be displayed on the list pages and the other are shown on the detailed information pages. In addition, for the biophysical binding data, ΔG, ΔH, -TΔS, t1/2, kon and koff are also collected into the database and only displayed on the detailed information page.

  • Cellular activities: IC50, EC50, GI50, ED50 and GR50 are collected into PROTAC-DB. Similarly, ED50 and GR50 are only displayed on the detailed information pages, not on the list pages.

  • Cell permeability: PAMPA and Caco-2 permeability data are collected into PROTAC-DB and only displayed on the detailed information pages.

Moreover, the biological activities of warheads and E3 ligands are also collected.

Considering the importance and limited number of crystal structures of ternary complex, we also provide the predicted ternary complex models for PROTACs with good degradation capacity using our PROTAC-Model method (J. Med. Chem. 2021, 64, 21, 16271-16281). PROTAC-Model is an integrative computational method by combining the FRODOCK-based protocol and RosettaDock-based refinement. Using the unbound structures, the FRODOCK-based protocol can generate the ternary complex structures with medium or high quality for 8 out of 14 test cases. With the refinement by RosettaDock, the cases with medium or high quality increase to 12.

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The warheads and E3 ligands here represent the structures integrated into PROTACs after modification, not the initial structures.

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