Step-by-step workflows for linker enumeration, ternary complex modeling, and degradation scoring.

You want to design a bifunctional degrader; these workflows take you from a warhead and E3 ligand through a linker library, ternary complex model, and degradation score. See PROTAC design on the platform for tool details.

PROTAC design quickstart

This guide covers three core workflows: enumerating linker libraries, modeling ternary complexes, and scoring degradation efficiency.

Workflow 1: Enumerate PROTAC linkers

Provide warhead and E3 ligand SMILES

Ask Ivy in chat (or submit the job directly with POST /api/v1/jobs; see the API reference):

Enumerate PEG linkers connecting this warhead to a CRBN ligand:
Warhead: CC1=CC(=O)N(C2=CC=CC=C2)C1=O
E3 ligand: O=C1CCC(N2CC3=CC=CC=C3C2=O)C(=O)N1

Ivy runs PROTAC linker enumeration to generate a diverse linker library.

Review the linker library

Field	Example Value
Total linkers	50
Linker length range	4-12 atoms
Scaffold types	PEG, alkyl, piperazine
Avg synthetic accessibility	3.2
Avg drug-likeness (QED)	0.35

Filter by properties (optional)

Filter the linkers to only PEG scaffolds between 6 and 8 atoms with SA score below 4

This narrows the library to the most synthetically accessible candidates in the desired length range.

Workflow 2: Model a ternary complex

Provide inputs

Model the ternary complex for this PROTAC with BRD4 and CRBN
PROTAC SMILES: [full PROTAC SMILES here]
POI PDB: 3MXF
E3 PDB: 4CI1

Or configure manually:

Parameter	Value
PROTAC SMILES	Full bifunctional molecule
POI structure	PDB ID or uploaded file
E3 ligase structure	PDB ID or uploaded file
E3 system	`CRBN`

Review the ternary complex

Field	Example Value
Buried surface area	1,850 A^2
Shape complementarity	0.72
Clash count	3
Interface residues (POI)	14
Interface residues (E3)	11
Feasibility score	0.81

Visualize the complex

The result includes a PDB file of the modeled ternary complex. View it in the Mol* 3D viewer on the canvas card to inspect the protein-protein interface and linker conformation.

Workflow 3: Score degradation efficiency

Submit for scoring

Score this PROTAC for degradation efficiency:
SMILES: [full PROTAC SMILES here]

Or configure:

Parameter	Value
PROTAC SMILES	Full bifunctional molecule
E3 system	`CRBN` or `VHL`
Ternary complex job ID	(optional, from Workflow 2)

Review degradation predictions

Metric	Predicted Value	Interpretation
DC50	18 nM	Potent degrader
Dmax	92%	Near-complete degradation
Hook effect risk	Low	No dose-response inversion expected
Cooperativity (alpha)	3.2	Positive cooperativity in ternary complex

Interpret the results

DC50 Range	Interpretation
< 10 nM	Highly potent degrader
10 - 100 nM	Potent degrader
100 nM - 1 uM	Moderate degrader
> 1 uM	Weak degrader

Dmax Range	Interpretation
> 90%	Near-complete degradation
70 - 90%	Good degradation
50 - 70%	Partial degradation
< 50%	Insufficient degradation

Workflow 4: End-to-end PROTAC design

Start with a target

Design a PROTAC to degrade BRD4 using a CRBN-based E3 recruiter.
Use the JQ1 warhead and pomalidomide as the E3 ligand.
Enumerate 30 linkers between 4 and 10 atoms.

Model top candidates

Model ternary complexes for the top 5 linkers by drug-likeness score

Score degradation

Score degradation efficiency for all 5 ternary complex models

Select leads

Ivy will rank candidates by DC50, Dmax, and synthetic accessibility, recommending the most promising leads for synthesis.

Next steps

See inputs for all parameters, SMILES formats, and constraint options
See outputs for result field descriptions and score interpretation
Use ADMET-AI for drug-likeness profiling of PROTAC candidates
Use AiZynthFinder for synthetic route planning

PROTAC design quickstart