What is fragment linking?

Learning objectives

After reading this article you will be able to:

  • Explain fragment-based drug discovery and the rule of three
  • Describe why linking fragments can give large affinity gains
  • Recognise the role of linker geometry and strain

Fragment-based drug discovery (FBDD) screens very small molecules, called fragments, instead of full drug-sized compounds. Fragments bind weakly — often only in the high micromolar to millimolar range — but efficiently, and they explore chemical space far better per compound tested.

The rule of three

Fragment libraries are often designed with the rule of three: molecular weight below 300 Da, calculated logP of 3 or less, and no more than 3 hydrogen-bond donors and 3 acceptors. Because fragments bind weakly, they are detected with sensitive biophysical methods such as X-ray crystallography, NMR or surface plasmon resonance, which also show where they bind.

Growing, merging and linking

  • Growing adds atoms to one fragment to reach new interactions.
  • Merging combines overlapping fragments into a single new core.
  • Linking connects two fragments that bind in neighbouring sites with a linker.

Why linking can pay off

When two fragments are joined, the combined molecule pays the cost of losing its freedom to move only once instead of twice. As a result, a well-linked molecule can bind much more tightly than the two fragments’ affinities would suggest when added together — an effect called super-additivity.

The catch is geometry. The linker must hold both fragments in their original binding positions and orientations without strain. A linker that is slightly too long, too short or twisted can lose most of the expected gain.

Finding the right linker

  1. Start from the two fragments’ 3D binding poses, ideally from crystal structures.
  2. Choose the attachment atoms on each fragment — usually hydrogens pointing towards each other.
  3. Search a library of linkers whose 3D ends match the distance and angles between those attachment points.
  4. Check that candidate products do not clash with the protein and are synthetically feasible, then refine and test.

The same 3D linker search is also a route to scaffold hopping: replacing the middle of an existing molecule while keeping both ends in place.

Last updated October 31, 2026

Keep learning

What are covalent drugs? Covalent drugs form a chemical bond with their target protein, usually through a reactive "warhead" that attacks a nearby amino acid such as cysteine. What is ADMET? ADMET stands for absorption, distribution, metabolism, excretion and toxicity — the properties that decide whether an active molecule can become a safe, effective drug. What is scaffold hopping? Scaffold hopping replaces the core of an active molecule with a different chemical framework that keeps the key interactions, to gain new IP, better properties or easier synthesis.

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