PROTAC design on the platform

Design bifunctional degraders that induce targeted protein degradation through the ubiquitin-proteasome pathway — enumerate linkers between a warhead and an E3 ligase ligand, model the three-body ternary complex for geometric feasibility, and predict degradation efficiency (DC50, Dmax, hook effect risk). Reach for these tools when your modality is targeted degradation rather than a conventional inhibitor. PROTAC design sits between an identified warhead and lead selection, feeding downstream into ADMET, retrosynthesis, and docking validation. See the Targets & Modalities overview for where this fits.

PROTAC design overview

The PROTAC toolkit provides a computational pipeline for designing Proteolysis-Targeting Chimeras -- bifunctional molecules that induce targeted protein degradation via the ubiquitin-proteasome pathway. The three tools cover the full design cycle: linker chemistry exploration, ternary complex feasibility assessment, and degradation efficiency prediction.

Architecture

Tool inventory

PROTAC design tools

Capabilities

Linker enumeration

Generate libraries of chemically diverse linkers connecting a warhead (POI binder) to an E3 ligase ligand. The tool interface exposes a linker_type choice (peg, alkyl, click, mixed) and a length_range, but neither currently reaches the backend — see the note above. The tool generates 3D conformers for each linker and ranks them by synthetic accessibility and drug-likeness.

Ternary complex modeling

Model the three-body complex formed when a PROTAC brings a protein of interest (POI) into proximity with an E3 ubiquitin ligase. The tool takes the POI structure (PDB or predicted), the E3 ligase structure, and the full PROTAC molecule as input. It evaluates whether the linker geometry allows productive protein-protein contact and scores the interface by buried surface area, shape complementarity, and clash count.

Degradation scoring

Predict how effectively a PROTAC will degrade its target protein. The scoring model estimates DC50 (concentration for 50% degradation), Dmax (maximum degradation percentage), and flags compounds at risk of the hook effect (reduced degradation at high concentrations due to binary complex competition). Scores incorporate linker properties, ternary complex geometry, and physicochemical descriptors.

PROTAC design fundamentals

Mechanism of action

Key design parameters

E3 ligase systems

When to use each tool

When to use other tools instead

Typical workflow

1. Select warhead (from docking or literature)
2. Select E3 ligase system (CRBN or VHL)
3. Enumerate linkers (protac_linker_enumerate)
4. Filter by drug-likeness and synthetic accessibility
5. Model ternary complexes for top candidates (protac_ternary_model)
6. Score degradation efficiency (protac_degradation_score)
7. Select leads for synthesis

Citations

Sakamoto KM, et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci USA. 2001;98(15):8554-8559. doi: 10.1073/pnas.141230798

Bondeson DP, et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat Chem Biol. 2015;11(8):611-617. doi: 10.1038/nchembio.1858

Churcher I. Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones? J Med Chem. 2018;61(2):444-452. doi: 10.1021/acs.jmedchem.7b01272

Chat usage

Example prompts

• "Design a PROTAC targeting BRD4 with a CRBN recruiter and PEG linker"
• "Enumerate 50 linkers between 6 and 10 atoms for this warhead and VHL ligand"
• "Model the ternary complex for my BET degrader"
• "What DC50 and Dmax can I expect for these PROTAC candidates?"
• "Compare alkyl vs PEG linkers for my PROTAC series"
• "Check hook effect risk for my top 5 candidates"

Workflow chaining

• Feeds into: ADMET prediction (absorption, metabolism), retrosynthesis (synthetic route), compound passport (comprehensive assessment), molecular docking (binding validation)
• Accepts from: Molecular docking (warhead pose), protein structure prediction (POI structure), compound search (E3 ligand scaffolds), literature search (known PROTAC designs)

FAQ

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