General pharmacology Other/Unclassified

PROTAC target-engagement and degradation dynamics

Reference paper ↗

A mechanistic pharmacodynamic model connecting PROTAC concentration, target and E3-ligase binding, catalytic degradation, protein turnover, and the high-concentration hook effect.

Therapeutic
Parameterized PROTAC
Modality
Targeted protein degrader
Target
generic POI, E3 ligase
Disease
Mechanistic target-degradation pharmacology
Model type
Other/Unclassified

Complete model workspace

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Parameters
10
States
3
Equations
3
Derived outputs
6

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Eq. 14 hook-model 6 h to 24 h RIPK2 degradation

How do binding affinity, catalytic rate, and PROTAC concentration determine target degradation and the hook effect? Explore this biological starting configuration through Mechanistic relative target protein, Hook-model relative target protein, Simplified target engagement, Steady-state maximum degradation.

Starting result

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Starting configuration

Time: 0–96 hour; step 1

InputDefaultAvailable range
PROTAC concentration68.9 nM34.45–103.4 nM
Target–PROTAC dissociation constant138 nM69–207 nM
PROTAC–E3 ligase dissociation constant3,100 nM1,550–4,650 nM
Catalytic degradation rate0.5 1/h0.25–0.75 1/h
Target-protein half-life45 h22.5–67.5 h

Expected readouts

Relative mechanistic degradation (dimensionless) · Relative hook-effect response (dimensionless) · Simplified target engagement · Steady state maximum degradation

Adjustable model parameters

This public explorer exposes 5 curated parameters. Sign in to edit all 10 declared model parameters.

More key parameters (1)

How the model represents the biology

A mechanistic pharmacodynamic model connecting PROTAC concentration, target and E3-ligase binding, catalytic degradation, protein turnover, and the high-concentration hook effect.

How do constant PROTAC concentration and two reduced PD formulations change target protein?A fixed PROTAC concentration drives two independent reduced pharmacodynamic lanes. In the mechanistic lane, algebraic target engagement adds catalytic protein loss while basal turnover restores target protein. In the hook lane, concentration sets an empirical hook-shaped steady state toward which a separate target-protein state relaxes.BIOLOGY OVERVIEWHow do constant PROTAC concentration and two reduced PD formulations change targetprotein?Fixed PROTAC levelScenario-defined concentrationSimplified engagementAlgebraic target/E3 termCatalytic degradationEngagement-driven target lossBasal recoveryProtein turnover towardbaselineMechanistic targetproteinRelative target-protein stateHook-shaped steadystateIndependent empirical laneHook-model targetproteinRelaxes toward hook predictionPRIMARY READOUTSMechanistic relative target proteinMechanistic relative targe…Hook-model target proteinHook-model target proteinSimplified engagementSimplified engagementHook-shaped degradationHook-shaped degradation

Solid arrows show modeled movement or change; two-headed arrows show reversible exchange; dashed arrows show modulation without material transfer.

Model scope: PROTAC PK or dosing, explicit binary or ternary-complex states, ubiquitin chains, proteasome states, and a causal connection between the two prediction lanes are not represented.

Modeled relationships (7)
  • Fixed PROTAC level → Simplified engagement: algebraic engagement (modulation)
  • Simplified engagement → Catalytic degradation: sets degradation (modulation)
  • Catalytic degradation → Mechanistic target protein: target loss (loss)
  • Mechanistic target protein → Basal recovery: baseline deficit (modulation)
  • Basal recovery → Mechanistic target protein: restoration (production)
  • Fixed PROTAC level → Hook-shaped steady state: biphasic curve (modulation)
  • Hook-shaped steady state → Hook-model target protein: relaxation target (modulation)

Modeled relationships: Fixed PROTAC level to Simplified engagement: algebraic engagement (modulation); Simplified engagement to Catalytic degradation: sets degradation (modulation); Catalytic degradation to Mechanistic target protein: target loss (loss); Mechanistic target protein to Basal recovery: baseline deficit (modulation); Basal recovery to Mechanistic target protein: restoration (production); Fixed PROTAC level to Hook-shaped steady state: biphasic curve (modulation); Hook-shaped steady state to Hook-model target protein: relaxation target (modulation).

Primary readouts: Mechanistic relative target protein; Hook-model target protein; Simplified engagement; Hook-shaped degradation.

Found a scientific issue? Email helpdesk@unibiointelligence.com with model ID haid_2023_protac_mechanistic_pd_framework.

Research use only — not for patient-specific prediction or dosing advice.

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