fragment hit
A fragment hit is the toehold at the bottom of a climb: a very small molecule that binds the target only weakly, but binds it in exactly the right spot and in a well-understood way, giving chemists a reliable place to start building. It does not act like a drug yet — it is a verified anchor point, not a finished medicine.
Fragment hits emerge from fragment-based campaigns, where small molecules (typically under ~300 daltons) are screened by sensitive biophysical methods. Their affinities are weak — micromolar to millimolar — but because they are so small, the binding they do achieve is highly efficient per atom, captured by a high ligand efficiency. Crucially, a fragment hit is usually accompanied by a structure (from X-ray or NMR) showing precisely how and where it sits in the binding pocket.
That structural knowledge is what makes a fragment hit valuable: knowing the exact binding pose lets chemists grow the fragment into unfilled space, link two fragments that bind neighboring subsites, or merge it with another scaffold, building potency rationally while keeping the molecule small and property-friendly. The weak starting affinity is the deliberate cost of beginning from a clean, efficient foundation.
An X-ray structure shows a 200-Da fragment binding at 500 µM, anchored by two hydrogen bonds in the active site; its high ligand efficiency makes it the chosen starting point for growing.
A weak but efficient, structurally defined fragment is the ideal foundation to build on.
Judge a fragment hit by ligand efficiency, not raw potency. A millimolar fragment that makes a few perfect contacts per atom is a far better starting point than a micromolar molecule that binds weakly for its large size.