What are hits, leads and clinical candidates?

Learning objectives

After reading this article you will be able to:

  • Tell the difference between a hit, a lead and a clinical candidate
  • List typical criteria used to promote a compound to the next stage
  • Explain why false positives are common in screening

Drug discovery projects use three words to describe how far a compound has come: hit, lead and candidate. Each step raises the bar for evidence.

Hit

A hit is a compound that shows activity against the target in a primary screen, often with modest potency (for example, an IC50 in the micromolar range). Screens produce many false positives: compounds that aggregate, react with the assay, fluoresce or are simply impure. A hit is therefore only a starting point until it is re-tested from fresh material and shows a dose–response curve.

Lead

A lead is a confirmed hit that belongs to a series chemists can improve. Typical expectations are:

  • reproducible activity with a clear structure–activity relationship (SAR) — small changes to the molecule change potency in understandable ways;
  • reasonable selectivity against related proteins;
  • acceptable early ADMET properties such as solubility and metabolic stability;
  • room to make analogues: synthetic routes and available building blocks.

Moving from hits to leads is called hit-to-lead. Searching for close analogues of a hit, by similarity or substructure, is one of the fastest ways to build early SAR without new synthesis.

Clinical candidate

After lead optimization, the team nominates a single compound (often with a backup) for preclinical development. A candidate must be potent in disease models, have a pharmacokinetic profile that supports the intended dose, an acceptable safety margin, and a route to manufacture at scale.

Useful metrics along the way

MetricWhat it tells you
IC50 / EC50Concentration giving half-maximal inhibition or effect in an assay.
Kd / KiBinding or inhibition constant; lower means tighter binding.
Ligand efficiencyBinding energy per heavy atom — rewards potency that does not come only from size.
Selectivity ratioPotency against the target compared with related off-targets.

Last updated October 31, 2026

Keep learning

What is virtual screening? Virtual screening uses computers to rank large compound libraries so that only the most promising molecules are bought, made or tested. What is chemical space? Chemical space is the set of all possible molecules; the drug-like part alone is estimated at around 10^60 compounds, far more than can ever be made. What is drug discovery? Drug discovery is the process of finding a molecule that changes a disease-relevant biological target safely enough to be tested in people.

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