Ref J4
Computational Service
Confidence Reported
Scoped After Feasibility Review
Service Overview
Macrocycles sit between small molecules and biologics: large enough to cover an extended interface, constrained enough to avoid paying full entropic cost, and — under the right conditions — capable of crossing membranes despite exceeding conventional property limits. We design macrocyclic molecules that combine peptide and small-molecule features, scan macrocyclisation positions and linker chemistry, generate conformational ensembles and optimise the permeability-versus-potency trade-off that governs this chemical space.
Key Features & Advantages
Chemistry Beyond Peptides
Designs combine peptidic and non-peptidic elements, giving access to linkers, heterocycles and backbone modifications that pure peptide chemistry cannot provide.
Conformational Ensembles, Properly Sampled
Macrocycle behaviour is governed by the accessible conformer population, so we use enhanced sampling rather than standard conformer generation, which systematically under-samples these rings.
Chameleonic Behaviour Modelled
Permeability assessment accounts for conformational switching between polar and shielded states, which is the mechanism by which successful macrocycles cross membranes.
Synthetic Route Assessed Early
Macrocyclisation is often the hardest step, so ring-closure feasibility and route practicality are evaluated during design rather than discovered at the bench.
Where This Service Is Used
1Targeting extended protein–protein interfaces with a synthetically tractable modality
2Designing orally available molecules in beyond-rule-of-five space
3Converting a peptide lead into a more drug-like macrocyclic scaffold
4Constraining a flexible small molecule to improve potency and selectivity
5Exploring novel chemical space around an established macrocyclic scaffold
Methods and Techniques Applied
1Target site analysis and definition of the shape and interaction requirements for the ring
2Macrocyclisation position and linker chemistry scanning with strain and geometry assessment
3Conformational ensemble generation with enhanced sampling methods suited to macrocycles
4Docking and complex modelling using macrocycle-capable protocols
5Permeability and property prediction with models appropriate to beyond-rule-of-five space
6Synthetic feasibility assessment focused on the ring-closing step and precursor availability
What We Need From You
1Target structure and site, or the linear or peptidic lead to be macrocyclised
2Known SAR identifying which interactions must be preserved
3Property requirements: oral exposure, solubility, metabolic stability
4Available synthetic chemistry and any preferred macrocyclisation approach
What You Receive
1Designed macrocycles with full structures and ring chemistry specified
2Conformational ensembles with population analysis
3Complex models with interaction analysis for the bound conformation
4Predicted permeability and property profiles with the associated risks stated
5Synthetic feasibility assessment with a proposed route for the leading designs
What We Compute and Report
1Conformational ensembles with populations for each accessible ring state
2Docked poses in the target site using macrocycle-capable protocols
3Permeability estimates accounting for conformational shielding behaviour
4Ring strain and macrocyclisation feasibility per closure position
5Property profile across the beyond-rule-of-five space with domain caveats stated
Questions We Are Asked Before Scoping
Are macrocycles orally available?
▸Some are, and most are not. Oral exposure requires specific hydrogen-bond donor counts, conformational shielding and lipophilicity balance. We predict the risk honestly rather than treating the modality as inherently oral.
Is docking reliable for macrocycles?
▸Less so than for rigid small molecules, because ring flexibility challenges both sampling and scoring. We use macrocycle-specific protocols and support conclusions with simulation.
How hard are these to synthesise?
▸Ring closure is frequently the limiting step and yields vary widely. Feasibility assessment is part of the design work so the delivered set is weighted toward makeable chemistry.
Interpretation and Limitations
Computational predictions prioritise hypotheses; they do not independently establish binding, biological activity, therapeutic efficacy, safety or clinical validity. Performance depends on input quality, target class, the structural evidence available and the applicability domain of the selected methods. Scores used for ranking are comparative devices and should not be read as measured quantities. All 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
An extended interface needs covering with chemistry more drug-like than a peptide
Oral exposure in beyond-rule-of-five space is the objective
A peptide lead should be converted into a more synthetically tractable scaffold
Consider another service when
A purely peptidic ring is acceptable and faster to make
Cyclic Peptide Design The pocket is small and enclosed
De Novo Small Molecule Design 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.
Standard conformer generation under-sampling the ring
Enhanced sampling is used, because ordinary conformer generators systematically miss accessible macrocyclic states.
Permeability predicted with models trained on small molecules
Beyond-rule-of-five models are applied, including conformational shielding behaviour, with domain limits stated.
Designs whose ring-closing step is impractical
Macrocyclisation feasibility and precursor availability are assessed during design, since ring closure is usually the hardest step.
A Worked Example
Converting a peptide lead into a macrocyclic scaffold
The situation
The peptide was active but unstable, and the team wanted chemistry that a medicinal chemistry group could optimise.
What the work involved
The pharmacophore was extracted from the peptide complex, macrocyclisation positions and non-peptidic linkers were enumerated, ensembles were generated, and permeability was predicted for each design.
What came back
Thirty macrocycles preserving the three key contacts, ranked by predicted permeability and ring-closure feasibility, with routes sketched for the eight most accessible.
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.
Service Workflow
1
Scientific Consultation
We discuss the objective, the decision it supports and the data you hold. Nothing is quoted before we understand what the result has to answer.
2
Feasibility Review
We check that the data, target class and available structural evidence can support the proposed 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
Computation and QC
The analysis runs on pinned tool versions in a containerised environment, with quality checkpoints and method comparison where that is informative.
5
Report and Follow-Up
You receive the ranked results, the documented methods, the limitations and a proposed validation plan, plus support in interpreting them.
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