PROTAC Binding Kinetics Analysis Service
CD ComputaBio provides advanced computational modeling and simulation to evaluate the dynamic interactions between PROTAC molecules, target proteins, and E3 ligases to support drug discovery efforts in oncology, neurodegenerative diseases, and other fields.
What is PROTAC Binding Kinetics?
PROTACs (proteolysis-targeting chimeras) induce protein degradation by simultaneously binding a target protein and an E3 ubiquitin ligase, forming a ternary complex. Their catalytic mechanism allows sustained degradation without stoichiometric consumption. Binding kinetics (e.g., kon, koff, and ternary complex stability) critically influence degradation efficiency. Optimizing these parameters enhances potency while minimizing off-target effects, leveraging dynamic protein-PROTAC-ligase interactions for therapeutic advantage.
Fig. 1 Mechanistic and Kinetic Schematic of PROTAC-Mediated Protein Degradation. (Zhao H, et al., 2023)
Key Parameters of PROTAC Binding Kinetics Analysis
| Parameter |
Definition |
| Binary Binding Affinity (Kd) |
Equilibrium dissociation constant for PROTAC binding to POI or E3 individually. |
| Cooperativity Factor (α) |
Strength of synergistic effects in ternary complex formation. |
| Ternary Complex Dissociation Rate (koff) |
Rate at which PROTAC dissociates from the ternary complex. |
| Binding Pathway |
Sequence of PROTAC binding to POI or E3 ligase first. |
Our Services
CD ComputaBio provides end-to-end PROTAC binding kinetic analysis services, spanning from molecular binding dynamics to functional degradation efficiency, to resolve critical challenges like high-affinity/low-activity paradoxes and species compatibility gaps. Our integrated platform accelerates degrader development by bridging mechanistic insights with predictive cellular activity models, reducing optimization cycles and clinical attrition risks.
Binding Affinity Prediction
We adopt molecular docking and free energy perturbation (FEP) calculations to evaluate PROTAC-induced ternary complex stability. Interaction energy analysis between PROTACs, target proteins, and E3 ligases quantifies binding affinities and cooperative effects, guiding identification of optimal molecular configurations for targeted degradation.
Off-Target Binding and Selectivity Profiling
We integrate ensemble docking simulations with advanced machine learning-based virtual screening algorithms to systematically predict and characterize PROTAC off-target interactions. This dual computational strategy synergistically combines structural insights with predictive analytics, effectively minimizing off-target protein degradation risks while quantitatively enhancing therapeutic selectivity.
The Process of PROTAC Binding Kinetics Analysis Service
Project Initiation & Consultation
We start with a detailed discussion to align on your PROTAC design objectives, target proteins, and desired kinetic parameters, ensuring a customized analytical strategy.
1
Data Collection & Molecular Profiling
Our experts gather and preprocess structural, biochemical, and kinetic data for your PROTAC, including target-E3 ligase interactions, to build robust computational models.
2
Multi-Scale Binding Kinetics Modeling
Using molecular dynamics simulations, machine learning, and quantum mechanical calculations, we predict on/off rates, residence times, and ternary complex dynamics to uncover kinetic bottlenecks.
3
Analysis & Optimization Report
You receive an actionable report with kinetic profiles, structural optimization strategies, and prioritized recommendations to improve PROTAC binding efficiency and therapeutic outcomes.
4
Application Scenarios
- Early-Stage Discovery: High-throughput screening of PROTAC libraries with ideal kinetic signatures.
- Mechanistic Validation: Mechanistic investigation of degradation efficiency variations (e.g., POI-PROTAC-E3 conformational shifts).
- Preclinical Development: Prediction of candidate molecule behavior under physiological conditions to mitigate clinical trial risks.
Technical Advantages
Multi-Dimensional Profiling
Multi-dimensional profiling of PROTAC binding kinetics (kon/koff, KD, ternary complex stability) through hybrid computational modeling and SPR/ITC experimental validation.
Cross-Platform Integration
Seamless integration of molecular dynamics simulations with cellular activity data to bridge in silico predictions and biological outcomes.
Customized Solutions
End-to-end solutions spanning from early PROTAC screening to species-specific preclinical optimization, addressing selectivity and translational challenges.
CD ComputaBio leverages advanced molecular modeling, kinetic simulation, and machine learning technologies to provide innovative approaches and customized solutions to accelerate the development workflow of highly effective PROTAC therapeutics. For detailed inquiries or collaboration opportunities, contact us for tailored computational support.
Reference:
- Zhao H.; et al. Kinetic Modeling of PROTAC-Induced Protein Degradation[J]. ChemMedChem. 2023, 18(24): e202300530.
* For Research Use Only.
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