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

Design bifunctional molecules (PROTACs) that recruit an E3 ubiquitin ligase to a target protein, inducing target ubiquitination and proteasomal degradation. PROTACs differ from traditional drugs: a stable ternary complex (target + PROTAC + E3) is required, not just target binding. The PROTAC field exploded post-2020 with clinical successes (ARV-471 estrogen-receptor degrader, ARV-110 androgen-receptor degrader). Postdoc-grade PROTAC design balances target ligand binding, E3 ligand binding, linker geometry (length, rigidity, chemistry), cooperativity (positive = ternary stable; negative = hook effect), and cell permeability (PROTACs are 800-1500 Da, often Lipinski-violating).

For target ligand design, see chemoinformatics/virtual-screening and chemoinformatics/admet-prediction. For linker-only enumeration, see chemoinformatics/reaction-enumeration. For generative linker design, see chemoinformatics/generative-design.

E3 Ligase Choice

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

Linker Design Principles

Decision Tree by Scenario

Ternary Complex Prediction Tools

# 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

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

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