DavidsonX – D001x – Medicinal Chemistry Chapter 10 – Lead Discovery Part 5 – Filtering Hits Pt 3 Video Clip – Other Lead Selection Criteria In the category of filtering hits, we have already discussed the presence of functional groups and the application of molecular indexes. These are both simple tests that can be performed by visual inspection of the hits. Other hit prioritization criteria, however, require experimentation. One experimental test is metabolism. The hit can be subjected to the different CYP enzymes to determine which, if any, of the CYP enzymes metabolize the hit. Remember from section 5 of Chapter 8 that some CYP enzymes, e.g. CYP2C9, show variability in activity across a patient population. If a hit is metabolized exclusively by one of these variably active forms of CYP, the hit may be deemed less attractive. A related experimental test is metabolism inhibition. The hit can be tested to determine whether it inhibits the most relevant forms of CYP for drug metabolism. Again, recall from Chapter 8 that drugs that inhibit metabolism run a high risk for interacting with other drugs. The prospect of significant drug interactions can downgrade one hit relative to another. Hits are also screened for their on-target activity in the presence of human serum, which contains significant amount of proteins, especially albumin. Almost all drugs and hit bind to serum proteins. Serum protein binding by a drug decreases the amount of drug that is available to bind the target. Screening a molecule in the presence of serum, therefore, decreases the apparent activity of the drugs. Hits that are strongly affected by serum proteins are often deprioritized in the lead discovery stage. Cell permeability is another experimental test for hits. Cell permeability tests use Caco-2 cells, cancer cells that can form monolayers of cells that replicate the epithelial lining of the small intestines. Through cell permeability tests, the absorption of a hit can tested. Hits that are only poorly able to passively diffuse across cell membranes will not likely be advanced as leads. The last test we will cover is not experimental in nature. It is instead a legal matter. For a hit to be considered a lead, the hit must be patentable. The legal team in a drug company searches the international patent literature to determine which of the hits can be patented. It is not uncommon for the simple structure of a hit to be elaborated with the addition of an extra ring to make the hit distinct from compounds that are already known in the patent literature. In this way, chemists can gain access to new intellectual property space and allow a hit to be patentable. Because there are so many hurdles for a hit to clear, having a large number of hits is ideal. The few hits that can clear all these hurdles may be advanced as leads. Hits that satisfy the various criteria will likely have been modified somewhat from their original structure. It is common for a hit with a Ki of 1 μM to be modified and improved to an activity of 100 nM by the time it is named as a lead.
Published on May 6, 2014