What is PROTAC Builder?
PROTAC Builder is a web tool for assembling candidate PROTAC structures from target-binding warheads, linkers, and E3 ligase recruiters.
Resources
PROTAC Builder FAQ
PROTAC Builder helps users assemble candidate degrader structures from warheads, linkers, and E3 recruiters. This FAQ explains what the tool does, what it does not do, how to use it responsibly, and how it connects to examples, API workflows, downstream modeling, and sister discovery tools.
Generated candidates are design hypotheses. They still require chemical review, structure-aware interpretation, modeling where useful, and experimental validation before biological conclusions are drawn.
Scope and limitations
Builder inputs and outputs
API and examples
Responsible interpretation
Quick answer
PROTAC Builder is an assembly and workflow-preparation tool. It helps organize components, define
attachment points, generate candidate structures, and prepare downstream handoffs. It does not guarantee
degradation, biological activity, permeability, or synthetic success.
General questions
Who is PROTAC Builder for?
It is useful for medicinal chemists, chemical biologists, computational chemists, structural biology users, and researchers preparing degrader candidates for modeling or experimental follow-up.
What problem does PROTAC Builder solve?
It standardizes component selection, attachment-point thinking, candidate assembly, and downstream handoff so users can move from idea to reproducible degrader hypothesis more cleanly.
Does PROTAC Builder guarantee that a molecule will degrade a target?
No. Degradation depends on ternary complex formation, ubiquitination geometry, cell permeability, E3 expression, target context, and experimental validation.
Is PROTAC Builder a complete PROTAC discovery platform?
No. It is a preparation and assembly layer, not a full replacement for warhead discovery, recruiter discovery, ternary modeling, synthesis, or biological assays.
Using the builder
What inputs can I use?
The builder supports preset component workflows, recruiter and ligand identifiers where implemented, custom SMILES input for browser-based editing, and query-parameter launches used in examples and handoff flows.
Can I open the builder with a preselected ligand or recruiter?
Yes. Implemented entry points include /builder?ligand=DR7, /builder?ligase=CRBN_Y70, /builder?ligase=VHL_3JS, and /builder?smiles=CCCCC.
Can I use a custom SMILES string?
Yes, where the custom SMILES workflow is supported. The structure should still be inspected carefully because valid string parsing does not guarantee correct chemistry, correct attachment logic, or downstream bridgeability.
What are attachment atoms?
Attachment atoms are the atoms selected for linker connection on the warhead and recruiter sides of the design. They define where the linker leaves each bound ligand.
Why do attachment atoms matter?
They determine exit vectors, linker geometry, and whether downstream modeling is even meaningful. A chemically valid 2D assembly can still be a poor 3D hypothesis if the attachment atoms are wrong.
Can I edit or choose linker attachment points?
Yes. The builder includes browser-based editing steps so users can inspect and modify warhead, linker, and ligase-side structures before saving the components and generating a candidate.
What output formats are available?
The builder clearly exposes generated SMILES in the interface and downloadable SMILES output. MOL- and SDF-backed representations are also used in implemented editing, handoff, and batch workflows, with ZIP-style workflow bundles available in some scripted paths.
Warheads, linkers, and E3 recruiters
What is a PROTAC warhead?
A warhead is the target-binding ligand or motif that anchors the degrader to the protein of interest.
How should I choose a warhead?
Prefer known binding context, ligand-bound structures when available, solvent-exposed candidate modification atoms, and evidence that target engagement remains meaningful after derivatization.
When should I use Warhead Hunter?
Use Warhead Hunter when you need to inspect protein-bound ligands, RCSB structures, solvent exposure, or candidate modification atoms before bringing a warhead back into the builder.
What does the linker do?
The linker controls distance, flexibility, rigidity, polarity, bridgeability, and much of the geometric relationship between the target protein and the recruited E3 ligase.
How do I choose a linker?
Start with a small panel, vary length and chemistry, consider both flexible and rigid alternatives, and use downstream structural review rather than assuming one linker hypothesis will be enough.
What is an E3 ligase recruiter?
An E3 recruiter is the ligand that binds the recruited E3 ligase and defines the ligase-side anchor of the PROTAC.
When should I use E3 Ligandalyzer?
Use E3 Ligandalyzer when recruiter structure, scaffold diversity, solvent exposure, expression context, or ligase-side attachment geometry still needs exploration.
Are CRBN and VHL the only E3 ligases supported?
No. CRBN and VHL are common examples, but the builder data and recruiter-oriented workflows are not conceptually limited to those two ligases. Actual recruiter availability depends on the current deployment and data.
Warhead Discovery
Inspect target-bound ligands and candidate modification atoms before assembly.
Open warhead guideWarhead Hunter
Use atom-level solvent exposure mapping and RCSB-aware upstream discovery.
Open Warhead Hunter ↗Linker Design
Review linker classes, bridgeability ideas, and geometry-aware design patterns.
Open linker guideE3 Recruiter Discovery
Review recruiter-side structure and attachment-vector considerations.
Open recruiter guideE3 Ligandalyzer
Inspect recruiter ligands, scaffolds, structures, and attachment context.
Open E3 Ligandalyzer ↗V-LiSEMOD
Use viral protein-ligand structures and solvent-exposed moieties for viral-target workflows.
Open V-LiSEMOD ↗Examples and query parameters
Where can I find example workflows?
See the Examples page for launchable builder workflows and cross-site handoff patterns.
Are the examples validated degraders?
No. They are workflow examples and reproducible entry points, not claims of validated degradation unless another page explicitly documents that status.
How do I build an HIV protease target PROTAC example?
You can start from the implemented route /builder?ligand=DR7, which preloads a HIV protease target ligand entry into the builder workflow.
How do I start with CRBN or VHL?
Use /builder?ligase=CRBN_Y70 or /builder?ligase=VHL_3JS to open the builder with common recruiter examples preloaded.
How does PROTAC Builder connect to Warhead Hunter?
Warhead Hunter supports upstream inspection of target-bound ligands and candidate modification atoms. PROTAC Builder then uses the selected warhead and attachment logic for degrader assembly.
How does PROTAC Builder connect to E3 Ligandalyzer?
E3 Ligandalyzer helps users inspect recruiter ligands, scaffolds, bound structures, and attachment vectors before recruiter-side choices are carried back into the builder.
How does PROTAC Builder connect to V-LiSEMOD?
V-LiSEMOD helps users inspect viral protein-ligand structures and solvent-exposed moieties when the target context is viral and a structure-aware warhead is still being selected.
API and batch workflows
Can I use PROTAC Builder programmatically?
Yes. The site includes API-oriented routes plus helper pages such as API Builder and API Docs.
What is the API Builder?
API Builder is a helper page for preparing scriptable and batch-friendly payloads that connect builder-style workflows to the public route surface.
Where can I find the OpenAPI schema?
The site exposes both /openapi.json and /openapi.yaml for machine-readable API discovery.
Can I batch-generate PROTAC candidates?
Yes, where the batch routes are implemented. See Batch Workflows and the API docs for linker-library and assembled-candidate generation patterns.
How should I report or reproduce batch workflows?
Record component IDs, custom SMILES where used, query parameters, builder route, date or version context, selected linkers, attachment logic, and output artifacts so others can reconstruct the same run.
Downstream modeling
What should I do after assembling a candidate?
Review descriptors, geometry, linker bridgeability, ternary-complex plausibility, and your experimental plan rather than assuming the assembled candidate is ready for biological claims.
Does PROTAC Builder perform ternary complex modeling?
No. Its methodological role is assembly and handoff. Ternary modeling belongs in downstream workflows and should be interpreted as prioritization evidence rather than proof of degradation.
What is constraint-driven PROTAC design?
It is a geometry-aware design framing that emphasizes explicit anchors, exit vectors, linker bridgeability, and structure-aware ternary hypotheses. See Constraint-Driven PROTAC Design.
What is in silico PROTAC modeling?
It covers docking, restrained ternary construction, MD, learned re-ranking, and related computational prioritization workflows. See In Silico PROTAC Modeling.
What downstream tools should I use?
See Downstream Modeling for handoff methods and Benchmarking for reporting and reproducibility considerations.
What does benchmarking mean here?
Benchmarking means documenting modeling assumptions, splits, metrics, failure modes, and reproducibility practices rather than reporting isolated scores without workflow context.
Limitations and interpretation
Why can a molecule bind both proteins but fail to degrade?
Ternary geometry, cooperativity, ubiquitination positioning, target lysine presentation, cell permeability, E3 expression, target context, and assay conditions can all break the path from binding to degradation.
Can a low docking score prove degradation?
No. A docking score is only one computational signal and does not prove productive ternary formation, ubiquitination, or cellular activity.
Can a predicted ternary complex prove degradation?
No. A predicted ternary complex is a hypothesis that may help prioritize chemistry, but it is not proof of biological outcome.
Can a good DC50 alone define the best degrader?
No. Dmax, selectivity, hook effect, exposure, target engagement, cooperativity, and practical assay context also matter.
Is this medical or clinical advice?
No. PROTAC Builder is a research-oriented platform, not a clinical decision tool.
Should generated candidates be experimentally validated?
Yes. Assembly, descriptors, and modeling can prioritize candidates, but experimental validation remains necessary.
Troubleshooting
My custom SMILES does not load. What should I check?
Check that the SMILES is valid, reasonably encoded for URL use when passed by query parameter, chemically sensible for the editor, and not relying on unsupported assumptions about salts, stereochemistry, or attachment logic.
A query-parameter example does not preload correctly. What should I check?
Check the route, the exact identifier, URL encoding, whether the referenced data exists in the current deployment, and whether your browser session is showing the latest builder code.
An image or page link is broken. How should I report it?
Use the project contribution or contact path such as Submit Data / Contribute so the broken link or asset can be reviewed in context.
Where can I contribute data or feedback?
See Submit Data / Contribute for contribution and feedback paths.
Related resources
How to Build a PROTAC
Step-by-step practical guide for assembling and prioritizing candidate degraders.
Read build guideComponent Hubs
See how warheads, linkers, and recruiters fit together as one discovery workflow.
Open component hubsExamples
Launch reproducible builder examples and workflow starter routes.
View examplesAPI Builder
Prepare scriptable and batch-friendly builder workflows.
Open API BuilderMethods
Read the methodology page for scope, assembly logic, handoffs, and limitations.
Open methods pageDownstream Modeling
See what comes after assembly: geometry checks, ternary modeling, and prioritization.
Open downstream modeling