What is a macrocycle?
Learning objectives
After reading this article you will be able to:
- Define a macrocycle and recognise common macrocyclic drugs
- Explain why ring size and pre-organisation help binding
- Describe the main challenges of macrocycle drug design
A macrocycle is a molecule that contains a ring of at least twelve atoms. The ring can be built from amino acids (cyclic peptides), from polyketide chains like many natural antibiotics, or from fully synthetic building blocks.
Macrocycles you already know
| Drug | Type | Use |
|---|---|---|
| Erythromycin | 14-membered macrolide (natural product) | Antibiotic |
| Cyclosporin A | Cyclic peptide of 11 amino acids | Immunosuppressant, taken orally |
| Sirolimus (rapamycin) | Macrolide natural product | Transplant rejection, mTOR inhibitor |
| Lorlatinib | Synthetic macrocycle | ALK-positive lung cancer |
Why macrocycles bind difficult targets
Many disease-relevant proteins act through large, shallow surfaces, for example where two proteins touch (protein–protein interactions). Conventional small molecules are too small to grip these surfaces strongly. Macrocycles are larger, so they make more contacts, and the ring pre-organises the molecule: it is already close to the shape it needs for binding, so it loses less flexibility (entropy) when it binds than an equivalent open chain would.
Closing a ring can also improve selectivity and metabolic stability, which is why medicinal chemists sometimes “macrocyclise” an existing open-chain lead.
The challenges
- Drug-likeness. Most macrocycles fall outside Lipinski’s rule of five. See beyond rule of five.
- Permeability. Large polar molecules usually cross cell membranes poorly. Some macrocycles solve this by hiding their polar groups; see membrane permeability.
- Synthesis. Ring-closing steps can be low-yielding, so macrocycle libraries have historically been small.
- Modelling. A big, flexible ring has many conformations, which makes 3D modelling and docking harder than for rigid small molecules.
Pyxis Discovery specialises in macrocyclic chemistry. Its web-shop lets researchers search in-stock and virtual macrocycle libraries alongside small molecules, and dock the results against their target.
Last updated October 31, 2026
Put it into practice
Screen, dock and order compounds in one place
Pyxis Discovery combines macrocycle and small-molecule libraries with similarity search, docking and structure prediction in the browser.