Computational Service
Protein Degrader
Scoped After Feasibility Review
Service Overview
Degrader programmes are expensive to run empirically, and the early decisions — is this target degradable, which ligase, which warhead — set most of the cost that follows. We assess target degradability from lysine accessibility, turnover and surface compatibility, shortlist E3 ligases on expression and structural grounds, and run virtual screening or ligand triage to find warhead chemistry. The output is a reasoned starting point rather than a list of compounds to make on hope.
Key Features & Advantages
Degradability Assessed Before Chemistry
Lysine availability, surface accessibility, protein half-life and known ubiquitination sites are examined first, because a target that cannot be productively ubiquitinated will not be rescued by better linkers.
Ligase Choice Reasoned, Not Defaulted
CRBN and VHL are the obvious starting points but not always the right ones. Tissue expression, surface complementarity with your target and resistance liabilities are weighed explicitly.
Warhead Triage
Existing binders are assessed for exit vectors that can carry a linker without destroying affinity, and virtual screening is applied where no suitable binder exists.
Screening Output Interpreted
Where you already have screening data, we analyse it for structure–degradation relationships rather than treating potency and degradation as the same signal.
Where This Service Is Used
1Deciding whether a target is worth a degrader programme at all
2Selecting the E3 ligase and warhead chemistry before linker work begins
3Finding new warhead chemistry when the available binder has no usable exit vector
4Triaging hits from a degrader screen into series worth optimising
5Assessing whether a resistance mechanism can be overcome by switching ligase
How the Work Is Performed
1Target assessment: surface lysine distribution, accessibility, turnover rate and known modification sites
2E3 ligase shortlisting from expression data, structural compatibility and available chemistry
3Warhead binding site analysis with exit vector identification for linker attachment
4Virtual screening or ligand-based searching where no suitable warhead exists
5Protein–protein docking of target and ligase to test whether productive geometries exist
6Analysis of existing screening data for structure–degradation relationships
What We Need From You
1Target identity and structure, with any known binders and their binding modes
2Cell system and tissue of interest, which bear on ligase expression assumptions
3Existing degrader or screening data, including compounds that failed to degrade
4Programme constraints: chemistry available, timeline and the decision the work must support
What You Receive
1Degradability assessment with the evidence for and against pursuing the target
2Ranked E3 ligase shortlist with the reasoning for each candidate
3Warhead recommendations with exit vector analysis for linker attachment
4Virtual screening results where new chemistry was sought, with poses and interaction analysis
5A written recommendation on whether and how to proceed, including when not to
Questions We Are Asked Before Scoping
Can you predict whether our target is degradable?
▸We can assess the structural and biological factors that make degradation plausible and identify targets that clearly lack them. Degradability ultimately depends on cellular context and is confirmed empirically.
Do we need a co-crystal structure to start?
▸No, but knowing the warhead binding mode matters a great deal, because exit vector choice depends on it. Where no structure exists we model the complex and treat the vector analysis as provisional.
What if no usable warhead exists?
▸Then virtual screening or de novo design for a binder with a suitable exit vector becomes the first step, and we would scope that before any degrader chemistry.
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
A decision is needed on whether a target is worth a degrader programme at all
E3 ligase and warhead chemistry must be chosen before linker work starts
Existing screening data needs interpreting for structure–degradation relationships
Consider another service when
Target, ligase and warhead are already fixed
Protein Degrader Design & Synthesis The question is why an existing degrader behaves as it does
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.
A programme started on a target that cannot be productively ubiquitinated
Lysine accessibility, turnover and surface compatibility are assessed before chemistry is committed.
Warhead chosen without a usable exit vector
Exit vector analysis is run on the binding mode, and where no vector exists, finding a new binder becomes the first step instead.
Ligase selected by habit
Expression, surface complementarity and resistance liabilities are weighed, and the reasoning is documented per candidate.
A Worked Example
A no-go recommendation that saved a year
The situation
A team wanted to start a degrader programme on a target with a good inhibitor series.
What the work involved
Surface lysine distribution and accessibility were mapped, protein turnover was assessed, and target–ligase docking was run for the plausible ligases.
What came back
Accessible lysines were confined to a face that no modelled ternary arrangement could present to a ligase. The recommendation was not to proceed, with the specific evidence stated.
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.
A 22% confirmed hit rate from docking 138 million compounds
In a landmark 2019 study, ~138 million make-on-demand compounds were docked against the dopamine D4 receptor. Of 549 compounds selected and tested, 122 were confirmed active — a 22% hit rate — including ligands in the sub-nanomolar range. The same work screened ~99 million compounds against AmpC β-lactamase, where 5 of 44 tested compounds were confirmed (11%), one of which was among the most potent non-covalent AmpC inhibitors reported at the time.
Lyu et al., Nature, 2019 ↗Hit rate rises with rank, which is why library scale matters
The same body of work showed that the probability of a compound being confirmed active increases as its docking rank improves, and that larger libraries push better-scoring molecules into the selected set. This is the practical argument for screening make-on-demand space rather than a physical catalogue — and also the reason scoring accuracy, not library size alone, remains the limiting factor.
Lyu et al., Nature, 2019 ↗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