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Drug Discovery → Hit Discovery

Hit Discovery

A “hit” refers to molecules that bind to the target and influences its function (i.e., enzyme inhibitors, receptor antagonists). In this case, target refers to any reproducible assay thought to be predictive of disease response. For a compound to be deemed a “hit”, certain criteria need to be assessed:

  • Reproducible dose-response effect in the primary assay
  • Confirmed structure and purity
  • Activity in a secondary assay versus the target
  • Selectivity: The “hit” needs to be selective enough versus defined ‘anti-targets’ to be promising for optimization
  • Synthetically tractable for Structure Activity Relationship (SAR) development
    • SARs relate the chemical structure of a molecule with its biological activity. This is an extremely important part of the drug discovery process and it is carried out iteratively through the subsequent stages
      1. Analysis of a SAR identifies structural modifications that could potentially enhance the drug candidate’s biologic activity or potency
      2. Computer-based models may be used to suggest how structural or chemical modifications may affect activity
      3. Different isomers of the drug candidate may be identified that could lead to changes in activity, potency or toxicity
      4. This serves as a starting point for lead optimization because it can point to certain modifications that will enhance a key aspect of the molecule
  • A common technique used in this part of the process is high throughput screening (HTS)
    • Rapidly assesses the activity of a large number of compounds or extracts on a given target. The term HTS is used when assays are run in a parallel fashion using multi-well assay plates (96-, 384-, 1536-well). Assays run in 1536-well plates with minuscule volumes (single-digit microliter to nanoliter scale) are sometimes referred to as ultra-high-throughput screening or UHTS
    • HTS/UHTS commonly involves semi-automation or full automation for liquid handling, sample preparation, running of the actual assays, as well as data analysis. HTS laboratories frequently employ robots and the latest detection technologies for assay readouts