protac-degraders

<!-- metadata: category: chemoinformatics oversight: low version: 1.0.0 author: Pradyumna Jayaram tags: [chemoinformatics, research] difficulty: intermediate -->

Version Compatibility

Reference examples tested with: PRosettaC (web service), DeepTernary 1.0+, AlphaFold3 (constraints-enabled), Boltz-1 / Boltz-2, RDKit 2024.09+, OpenMM 8.1+ (for ternary MD).

Before using code patterns, verify installed versions match. If versions differ:

• Python: pip show <package> then help(module.function) to check signatures

If code throws ImportError, AttributeError, or TypeError, introspect the installed package and adapt the example to match the actual API rather than retrying.

PROTAC and Bivalent Degrader Design

Hard rules

1. No fabricated citations. Every cited work must resolve to a verifiable
2. No claim without provenance. Every quantitative or factual claim
3. No silent failure. Every script invocation, API call, or tool use must declare its exit status and what to do on non-zero. A skill that silently swallows errors is a violation.

When to use

Load this skill when the user asks a question that matches its declared trigger conditions (see the frontmatter description for the most common ones). Do not load it for questions outside its scope — defer to the appropriate ORS skill instead.

When NOT to use

Do not load this skill if the question is in a sibling skill's domain (see ## Cross-references), if the user explicitly asks for a different tool, or if the task is outside the skill's declared category.

E3 Ligase Choice

E3 ligase	Ligand series	Best at	Limitations
VHL	VL-269	Surface-exposed targets	Tissue-restricted expression
CRBN (cereblon)	thalidomide, pomalidomide	Broad tissue expression	Off-target neosubstrates (IKZF1, SALL4)
IAP (XIAP, cIAP1)	SMAC mimetics (LCL161)	Apoptotic / IAP targets	Limited target scope
MDM2	nutlin / idasanutlin	TP53 pathway	Limited target diversity
KEAP1	DDB1-DCAF15-Keap1	NRF2 pathway	Specialized use
RNF114	EN450	Newer; under exploration	Limited tooling

Decision: For first-generation PROTAC, CRBN (cereblon) is the most-developed. VHL is second-most-developed (more selective; tissue-restricted).

Linker Design Principles

Property	Range	Effect
Linker length	8-30 atoms	Critical; geometry-dependent
Linker rigidity	Flexible (PEG) vs rigid (piperazine)	Higher rigidity reduces entropy penalty
Linker chemistry	PEG, alkyl, piperazine, triazole, ether, amide	PEG common; rigid for tighter binding
Click chemistry compatibility	Triazole compatible	Easy synthesis
MW range	PROTAC 800-1500 Da	Lipinski-violating but accepted
Polar atoms	1-5 per linker	Permeability vs solubility balance
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Critical: "Goldilocks linker length" is target-specific. Too short = ternary clash; too long = ternary entropy too high. Typically 12-20 atoms for surface-exposed targets.

Decision Tree by Scenario

Goal	E3 / linker	Tools
First-generation PROTAC, surface-exposed target	CRBN + PEG linker (10-15 atoms)	PRosettaC for ternary prediction
Selective degrader (avoid off-target)	VHL + rigid linker	PRosettaC + cellular validation
BTK / IAP family targets	IAP-based PROTAC	Standard pipelines
Novel target, no cryptic	Multiple E3 / linker variants	Combinatorial design + PRosettaC
Molecular glue (non-PROTAC)	CRBN-based	Distinct mechanism

Ternary Complex Prediction Tools

Tool	Approach	Strength	Fails when
PRosettaC	Rosetta-based protein-protein docking	Industry standard	Slow; needs crystal structures
DeepTernary	ML-based	Fast; no crystal required	Limited accuracy for new targets
AlphaFold3 (with constraints)	Foundation model	Excellent when co-crystal of binary available	API-restricted
Boltz-1 / Boltz-2	Foundation model	Open source; multimer support	Larger than AF3 in some benchmarks
MOE	Commercial	GUI + scriptable	License cost

# Conceptual PRosettaC workflow
# prc -target target.pdb -e3 crbn.pdb -linker-protac protac.smi \
#     -output ternary.pdb

Cooperativity (Alpha)

Cooperativity measures whether the PROTAC binds target+E3 more tightly than the sum of binary bindings:

alpha = Kd(binary) / Kd(ternary) * 1

alpha	Interpretation	Action
> 10	Strong cooperativity	Excellent candidate
1-10	Moderate	Iterative optimization
< 1	Negative (anticooperative)	Re-design

Cooperativity > 5 is desirable for cellular activity. Negative cooperativity suggests linker too long or attachment geometry wrong.

DC50 / Dmax Characterization

• DC50: concentration for 50% target degradation
• Dmax: maximum degradation achievable (0-100%)
• Hook effect: PROTAC activity drops at high concentration (binary complexes dominate over ternary)

# Cellular degradation assay (Western blot or reporter)
# Measure DC50 (e.g. 10 nM) and Dmax (e.g. 90% at 1 uM)
# If Dmax plateaus < 80% at high conc, check hook effect

PROTAC Databases

Database	URL	Compounds
PROTAC-DB	http://protacdb.weizmann.ac.il/	~5000 published PROTACs
EU-OPENSCREEN	Various	Curated

Per-Tool Failure Modes

Hook effect at clinical dose

Trigger: Bell-shaped degradation curve in cellular assay.

Mechanism: At high PROTAC concentration, binary complexes dominate over ternary; productive degradation only happens at moderate concentration.

Symptom: Dmax falls at high PROTAC; therapeutic window narrow.

Fix: Reduce dose; or re-design linker to favor ternary.

Negative cooperativity

Trigger: PROTAC binds target with similar Kd to parent ligand, but ternary unstable.

Mechanism: Linker geometry puts target and E3 in unfavorable orientation.

Symptom: Cellular degradation absent despite binary binding.

Fix: PRosettaC-driven linker re-design; consider rigid linker.

Cellular permeability poor

Trigger: PROTAC active in lysate but not in cells.

Mechanism: MW > 1000 Da often violates cellular permeability rules.

Symptom: Cellular DC50 >> biochemical Kd.

Fix: Reduce MW; switch to rigid linker (smaller); use "PROTAC-to-drug" libraries optimized for permeability.

References

• Békés et al. -- PROTAC review.
• Gadd et al. -- BRD4 degraders.
• Bondeson et al. -- CRBN-based PROTACs.

Related Skills

• chemoinformatics/virtual-screening - Target ligand design
• chemoinformatics/retrosynthesis - Synthesizability
• chemoinformatics/generative-design - Generative linker design
• chemoinformatics/covalent-design - Covalent E3 ligands

Cross-references

Other skills in this category:

• admet-prediction
• conformer-generation
• covalent-design
• docking-rescoring
• free-energy-calculations
• generative-design
• molecular-descriptors
• molecular-io
• molecular-standardization
• pharmacophore-modeling
• pose-validation
• qsar-modeling
• retrosynthesis
• scaffold-analysis
• shape-similarity
• similarity-searching
• substructure-search
• virtual-screening

Changelog

• 1.1.0 (migration) — Bulk-migrated to v0.4.0 schema: canonical metadata block, base Hard rules, Cross-references. Body content unchanged; author should review and fill in any domain-specific extensions to the Hard rules.
• 1.0.0 — Initial release.