Why should users inspect components before assembly?

Component inspection matters because bound pose, attachment atoms, linker reach, recruiter geometry, and downstream modeling readiness all affect whether an assembled degrader hypothesis is even plausible.

How does Warhead Hunter support PROTAC design?

Warhead Hunter helps users inspect ligand-bound protein structures, map atom-level solvent exposure, identify candidate attachment atoms, and carry target-aware warhead ideas back into PROTAC Builder.

How does linker design fit into the component workflow?

Linker design connects the warhead and the recruiter, and it controls reach, flexibility, rigidity, polarity, bridgeability, and much of the degrader's ternary-complex feasibility.

How does E3 Ligandalyzer support recruiter discovery?

E3 Ligandalyzer supports structure-first recruiter selection by helping users compare recruiter ligands, scaffold diversity, solvent exposure, bound poses, and ligase context before assembly.

What happens after component assembly?

After component assembly in PROTAC Builder, users should carry structured candidates into downstream modeling, scoring, and experimental validation rather than assuming assembly alone is enough.

Discovery Hubs

PROTAC Component Hubs

PROTAC design starts with three component decisions: a target-binding warhead, a linker, and an E3 ligase recruiter. Each component defines a different part of the final degrader’s geometry, physicochemical burden, and downstream modeling feasibility.

This page is meant to feel like a component map rather than a link list. It shows where each discovery question lives, which sister tool supports it best, and how users should move from component inspection into PROTAC Builder assembly and then into downstream modeling and validation.

Warhead pose Linker bridgeability Recruiter geometry Assembly-ready components

Start with Warheads Explore Linkers Explore E3 Recruiters Launch PROTAC Builder

Mechanism overview showing a PROTAC bringing a protein of interest together with an E3 ligase, leading to ternary complex formation, ubiquitination, and proteasomal degradation. — **Component logic in context.** A PROTAC only works as a system when the warhead, linker, and E3 recruiter together support a productive ternary complex and downstream degradation pathway. Source: Osman, Thompson, Jörg, and Scanlon, *Biochemical Journal* (2025), doi:10.1042/BCJ20243018.

Quick answer: what are PROTAC component hubs?

PROTAC component hubs are workflow pages that help users inspect and prepare the three core degrader building blocks: the POI-binding warhead, the linker, and the E3 recruiter. Each hub focuses on the information needed before assembly, including binding pose, attachment atoms, linker reach, geometry, scaffold context, and downstream modeling readiness.

The three core PROTAC components

Warhead / POI ligand

The warhead binds the protein of interest and defines the target-facing anchor. It needs binding-pose context, a plausible solvent-exposed attachment vector, and enough chemical tolerance to support derivatization.

Strong binding alone does not guarantee a useful degrader warhead if the editable atoms are buried or geometry-breaking.

Warhead discovery Warhead Hunter ↗

Linker

The linker connects the warhead and recruiter and controls distance, flexibility, rigidity, polarity, geometry, and bridgeability.

It should be treated as a design hypothesis rather than a passive spacer because it can make or break ternary-complex formation.

Linker design Constraint-driven design

E3 recruiter

The recruiter binds an E3 ligase and defines the ligase-facing anchor and exit vector. Recruiter choice affects ternary geometry, selectivity, cell context, and off-target risk.

CRBN and VHL are common examples, but recruiter selection should still be structure-aware and context-aware.

E3 recruiter discovery E3 Ligandalyzer ↗

From component selection to PROTAC assembly

Define the biological target and the question degradation should answer.
Identify or inspect target-binding warheads in Warhead Hunter.
Confirm at least one plausible solvent-exposed attachment atom.
Select an E3 ligase recruiter and inspect recruiter-bound context in E3 Ligandalyzer.
Confirm recruiter attachment vector, scaffold context, and if relevant, expression context.
Choose a linker panel guided by bridgeability hypotheses and the Linker Design hub.
Assemble candidate degraders in PROTAC Builder.
Export to Downstream Modeling for geometry checks, ternary modeling, and prioritization.
Use Benchmarking and experiments to validate conclusions instead of relying on assembly alone.

Warhead discovery

Warhead Hunter is the upstream discovery layer for target-binding ligands. It maps atom-level ligand solvent exposure in protein-bound structures, helps users search RCSB by PDB ID or by protein and keyword query, and returns synchronized 2D and 3D views that support attachment-site inspection.

Bound-pose context helps users understand which atoms are buried and which remain solvent-facing.
RCSB Scout supports both known-PDB and protein or keyword search modes.
Exposure mapping is useful design evidence, but not a guarantee of a successful PROTAC warhead.

Open Warhead Hunter ↗ Search RCSB Scout ↗ Launch a Warhead Hunt ↗ View Warhead Examples ↗

Warhead Hunter homepage showing structure-guided warhead discovery, atom-level solvent exposure mapping, result outputs, and launch options. — **Warhead Hunter hub.** Warhead Hunter converts ligand-bound protein structures into atom-level solvent exposure maps and downloadable results that can support target-aware warhead planning.

Linker design

Figure summarizing PROTAC linker classes and the diversity of flexible and more rigid linker strategies. — **Linker classes.** Linker strategy influences reach, conformational freedom, polarity, and much of the geometric feasibility that connects warheads and recruiters into one degrader hypothesis. Source: Dong et al., *Acta Pharmaceutica Sinica B* (2024), doi:10.1016/j.apsb.2024.04.007.

Linker design is the bridge between component discovery and ternary-complex modeling. Flexible linkers can sample productive conformations but may pay entropic or permeability costs. Rigid linkers can preserve geometry but may fail quickly when exit vectors are wrong.

Length should usually be tested systematically instead of guessed once.
Polarity and molecular burden still matter because PROTACs are already large molecules.
Bridgeability should be documented before expensive downstream modeling begins.

Read Linker Design Guide Constraint-Driven Design Downstream Modeling

E3 ligase recruiter discovery

E3 Ligandalyzer is the structure-first discovery layer for ligase-side selection. It helps users compare recruiter ligands, scaffold diversity, solvent exposure, bound poses, and expression-aware context before recruiter structures are carried into PROTAC Builder.

Recruiter selection should not be made only by habit or by the popularity of CRBN or VHL.
Bound structures and recruiter-side attachment vectors matter because they shape ternary geometry.
Export workflows support handoff into PROTAC Builder with selected attachment atoms.

Open E3 Ligandalyzer ↗ Explore Recruiters ↗ View Scaffold Dashboard ↗ Read E3 Recruiter Guide

E3 Ligandalyzer cover image showing structure-first E3 recruiter selection and geometry-aware recruiter analysis for PROTAC design. — **Recruiter-side context.** E3 Ligandalyzer supports structure-first recruiter inspection, scaffold review, solvent exposure awareness, and recruiter export planning before final degrader assembly.

Viral warhead discovery with V-LiSEMOD

V-LiSEMOD supports viral protein-ligand structure exploration and can help users find viral target-bound ligands and solvent-exposed moieties relevant to warhead discovery. It is especially useful upstream of PROTAC Builder when the target is viral and users need target-binding structural evidence before assembly.

Open V-LiSEMOD ↗ Read Warhead Discovery

From components to assembly

PROTAC Builder is where selected components become candidate degrader structures. It helps users select or import a warhead, select or import an E3 recruiter, choose or enumerate linkers, define attachment atoms, assemble candidates, and export structures for downstream modeling or batch workflows.

What it helps organize

Component boundaries, attachment atoms, assembled candidate structures, linker alternatives, and workflow handoff into modeling or API-based pipelines.

What it does not guarantee

Assembly is a design hypothesis. Productive degradation still requires geometry, downstream modeling where useful, and experimental validation.

Launch PROTAC Builder How to Build a PROTAC Open API Builder

Component readiness checklist

Warhead

Target is biologically justified.

Bound pose is known or modeled.

Attachment atom is solvent-exposed.

Key binding interactions are preserved.

Linker

Length range is reasonable.

Flexible and rigid alternatives are considered.

Polarity and molecular burden are considered.

Bridgeability hypothesis is documented.

E3 recruiter

E3 ligase is relevant to the cellular context.

Recruiter-bound structure or pose is available.

Recruiter attachment atom is plausible.

Scaffold and expression context have been reviewed.

Assembly

Components have defined boundaries.

Anchor atoms are documented.

Stereochemistry and protonation assumptions are preserved.

Downstream modeling and validation plan exists.

Common component selection mistakes

Warhead-side mistakes

Choosing a warhead only because it binds strongly, selecting a linker attachment atom from 2D alone, or losing attachment-atom context before assembly can undermine the whole degrader hypothesis.

Linker-side mistakes

Treating the linker as a passive spacer, using only one length, or ignoring polarity and bridgeability can make a plausible-looking design impossible in 3D.

Recruiter-side mistakes

Choosing CRBN or VHL only by habit, ignoring E3 expression, and skipping recruiter-side geometry or scaffold review can narrow the design space too early.

Workflow mistakes

Assuming assembled candidates will degrade, skipping downstream modeling, or treating component selection alone as proof of success can create false confidence.