Hit Discovery & Confirmation for Early Drug Discovery

Hit discovery and confirmation phase helps in the identification of molecules with activity against the target. This phase needs the development of compound screening assays, depending on the drug target.

Hit Discovery

A hit is a compound which has the desired activity in a compound screen. This activity should be confirmed upon retesting. The main motive is to identify molecules that interact with the drug target.

Main Approaches:

• High throughput screening (HTS)
  — screening of the entire compound library against the drug target
• Focused or knowledge-based screening
  — selecting from the chemical library smaller subsets of molecules with potential activity at the target protein
• Fragment screening
  — making very small molecular weight compound libraries which are screened at high concentrations
• Physiological screening
  — tissue-based approach with the response more in direction with the desired in vivo effect
  

Hit Confirmation: Assay Development

Various assays can be used for compound screening, ranging from biochemical to cell-based assays. The choice of the assay depends on the biology of the drug target protein, scale of the compound screen, the equipment infrastructure etc.

Factors required for assay development:

• Pharmacological importance of the assay
  — ability to identify compounds with the desired mechanism of action
• Reproducibility
  — is reproducible across assay plates, screen days and the length of the drug discovery programme
• Quality
  — pharmacology of the standard compound(s) falls within predefined limits
• Effects of compounds in the assay
  — not sensitive to the concentrations of solvents used in the assay
  

Hit Confirmation: Defining a hit series

Drug-like molecules must go through different phases to identify the hit molecule with a potency of 100nM – 5mM at the drug target.

The refinement process:

• Generating dose–response curves in the primary assay for each hit
• Examining the surviving hits in a secondary assay (if available)
• Generation of rudimentary SAR (structure–activity relationship) data and identifying the essential elements in the structure linked with the activity
• in vitro assays providing significant data with regard to absorption, distribution, metabolism and excretion (ADME) properties as well as physicochemical and pharmacokinetic (PK) measurements

Using the correct tools can help guarantee that after you’ve identified your novel target, you can create the right key to unlock it. We can support you with the innovation you need to identify, evaluate, and rank new lead candidates in a large screen and then confirm them with secondary assays and structure-activity relationships. Our goal is to help ensure only the strongest candidates make it past this stage of the drug identification and discovery process in order to fully optimize your pharmaceutical pipeline.