Computational Service
Protein Degrader
Scoped After Feasibility Review
Service Overview
Once target, ligase and warhead are fixed, degrader optimisation becomes a linker problem — length, rigidity, attachment vector and chemistry, each of which changes whether a productive ternary complex can form. We enumerate the design space systematically, model the resulting complexes, score them on interface quality and predicted cooperativity, and filter for the beyond-rule-of-five properties that determine whether the molecule will enter a cell at all.
Key Features & Advantages
Linker Space Enumerated Systematically
Attachment vectors, lengths, rigidity classes and chemistries are combined and evaluated together rather than explored one variant at a time at the bench.
Ternary Complexes Modelled And Simulated
Predicted complexes are refined and tested by molecular dynamics, because a geometry that looks reasonable in a static model frequently does not hold.
Cooperativity Assessed
Interface contacts between target and ligase are analysed to distinguish designs that merely tether from designs that stabilise a cooperative complex.
Permeability Treated As A Constraint
Degraders sit outside conventional property space. Permeability and solubility are predicted with appropriate models and used as design filters, not reported afterwards.
Where This Service Is Used
1Designing a first linker series once target, ligase and warhead are chosen
2Rescuing a series that binds both proteins but degrades poorly
3Optimising an existing degrader for permeability or metabolic stability
4Testing whether an alternative attachment vector improves ternary geometry
5Prioritising which of many possible linker variants are worth synthesising
How the Work Is Performed
1Attachment vector analysis on both warhead and ligase ligand, with chemistry compatibility checked
2Linker enumeration across length, rigidity and functional group composition
3Ternary complex prediction and refinement, followed by molecular dynamics stability assessment
4Interface and cooperativity analysis with binding energy decomposition
5Physicochemical and permeability prediction using beyond-rule-of-five appropriate models
6Retrosynthetic assessment and route sketching for the recommended designs
What We Need From You
1Target and ligase structures, with warhead and ligase ligand binding modes
2Existing degrader data: compounds made, degradation results, hook effect observations
3Chemistry available in house or through your synthesis partner
4Property constraints, including whether oral exposure is a requirement
What You Receive
1Ranked degrader designs with full structures and the linker rationale for each
2Ternary complex models with interface analysis and simulation-based stability assessment
3Predicted property and permeability profiles with the risk stated per design
4Retrosynthetic assessment with proposed routes for the recommended set
5A testing sequence stating which hypothesis each synthesised compound tests
Questions We Are Asked Before Scoping
How many linker variants should we synthesise?
▸Most first rounds run to fifteen to thirty. Degrader activity is not reliably predictable, so the purpose of the modelling is to make that round systematic rather than to replace it.
Can you predict the hook effect?
▸Not quantitatively. Modelling identifies designs likely to form cooperative complexes, which correlates with a wider effective window, but the hook effect is measured rather than predicted.
Do you perform the synthesis?
▸No. ICDMO is a computational CDMO. We design, model and prioritise; synthesis and biological testing are carried out by your team or a qualified partner.
Interpretation and Limitations
This is a computational (in silico) service. Designs and predictions prioritise hypotheses and direct experimental effort; they do not by themselves establish that an edit, construct, molecule or assay will perform as intended. Laboratory execution — editing, cloning, expression, synthesis and testing — is planned with you and carried out by your own team or a qualified partner. Deliverables are for research use only and are not intended for diagnostic or therapeutic use.
Is This the Right Service for You?
Choose this when
Target, ligase and warhead are fixed and the linker space must be explored systematically
A degrader series binds both proteins but degrades poorly
Permeability is limiting and the molecule must be redesigned within that constraint
Consider another service when
Degradability itself is still unproven
Protein Degrader Discovery & Screening Compounds exist and need characterising rather than designing
Degrader Assessment & Validation What Goes Wrong, and How We Handle It
These are the failure modes that produce confident-looking results which do not survive the next experiment. Each one is designed against rather than discovered afterwards.
Linker length varied while the attachment vector stays wrong
Attachment vectors on both ends are re-analysed first, since the wrong vector cannot be rescued by linker length.
Static ternary models taken as evidence of a stable complex
Predicted complexes are refined and simulated, and arrangements that do not hold are reported as failing.
Property assessment deferred until after synthesis
Permeability and solubility are predicted during design with beyond-rule-of-five models, and used as filters.
A Worked Example
Twenty-four linkers designed after six failed
The situation
The first six linkers produced strong binary binding and no degradation.
What the work involved
Both attachment vectors were re-analysed, ternary complexes were modelled and simulated across lengths and rigidity classes, and cooperativity was estimated from interface contacts.
What came back
The original vector oriented the ligase away from the target surface. Twenty-four redesigns were ranked by modelled complex stability, with predicted permeability reported for each.
Illustrative of the shape this work takes. Details are generalised, no client or target is identified, and scope and outcome vary with the system in question.
What Published Work Reports
The results below were published by independent groups and are cited to show what these computational approaches have achieved in the literature. They are not ICDMO project results, and outcomes vary substantially between targets, datasets and programmes. We do not promise comparable results for any particular project.
AI-designed molecules have now produced clinical-stage compounds
A compound designed by generative methods against an AI-nominated target completed a randomised Phase 2a trial in idiopathic pulmonary fibrosis, reporting a mean forced vital capacity change of +98.4 mL in the 60 mg once-daily arm against −20.3 mL for placebo over 12 weeks in 71 patients. The result shows that generative design can produce molecules that survive to clinical testing; it does not show that any individual generated series will.
Nature Medicine, 2025 ↗Service Workflow
1
Scientific Consultation
We discuss the objective, the decision it supports and the material and data you already hold.
2
Feasibility Review
We check that the target, system and available information can support the approach, and say plainly where they cannot.
3
Technical Proposal
Scope, methods, deliverables, timeline and price are confirmed in writing, together with the limitations we expect to report.
4
Design and Analysis
The design work runs on documented tools and parameters, with quality checks and alternatives compared where that is informative.
5
Delivery and Follow-Up
You receive the designs, the supporting analysis and a validation plan, plus support interpreting the results once the experiments run.
Service Process
1
Online Consultation
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2
Solution Matching
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3
Service Contract
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4
Project Execution
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5
Data Delivery
Specifications & Turnaround
Note: ICDMO delivers computational (in silico) services. Results prioritise hypotheses for testing; they do not by themselves establish binding, biological activity, efficacy or safety. All deliverables are for research use only and are not intended for diagnostic or therapeutic use. Downstream experimental work is scoped separately and executed through qualified partners.
Get a Custom Quote
Our scientific team responds within 24 hours with a detailed technical proposal and pricing tailored to your project.
Contact Us Online ConsultationStandard Deliverables
✓Sequence-verified final product
✓Full QC documentation
✓Certificate of Analysis (CoA)
✓Electronic data files
✓Project completion report
Why ICDMO?
Computational CDMO Focus
Reproducible, Versioned Pipelines
Confidence & Limitations Reported
Experiment-Aware Recommendations
Response Within One Business Day