Target Identification

Target Identification determines what is causing a disease. Discovery often begins with target identification. Drugs usually act on either cellular or genetic chemicals in the body, known as targets, which are believed to be associated with disease. Scientists use a variety of techniques to identify and isolate individual targets to learn more about their functions and how they influence disease. Compounds are then identified that have various interactions with the drug targets that might be helpful in treatment of a specific disease.

 

Scientists need to validate a target in order to determine what is causing a disease.

To make that determination, scientists first need to determine if the disease is an infectious agent or a host imbalance:

  • If it is an infectious agent that is causing the disesase, scientists need to find a target not in humans and go after that in the drug discovery process.
  • If it is a host imbalance disease, scientists then need to determine the cause:
    • Replace underactive protein (insulin)
    • Inhibit overactive protein (kinase)

The target process is very complex because the human genome (genetic space) is huge and there is a lot to search from.

Once scientists have identified the target, they need to determine if the target is druggable.

The following considerations define the drugability of the target:

  • Are there known small molecules that bind to the target?
  • Does the target have a site that looks like it will bind a small molecule (cavity, energetic hot-spot)?

Certain targets like to bind to small molecules. Some targets of great interest are:

  • GPCR
  • Kinases
  • Protease
  • P-P targets

Biological Considerations - The goal for oral drugs is to create a single daily dose  of <100 mgs per day.

In order to meet that goal, there are certain molecular properties which the compound is required to show:

  • Binding of the compound to the target with a great deal of potency (Kd<10nM)
  • Measure the potency of the compound in the cell (IC50< 100 nM)
  • T1/2 for clearance in blood >3 hours
  • Oral uptake >50% of drug

Chemical Considerations - General guidelines for oral drugs (chemical properties, Lipinski Rules):

  • Have a molecular weight of less then 500 Da
  • Good solubility (cLog P <5) – things that are not very soluble don’t dissolve very well
  • Fewer than 10 H-bond acceptors – are better at being orally active drugs
  • Fewer than 5 H-bond donors – are also better at being orally active drugs

Scientists then begin the search to find compounds that will engage the target.

 

Continue to Hit Identification / Target Validation >