Lecture 3

~100,000 compounds screened to get lead compounds

Large library of compounds

Restrict to a smaller # of compounds that are structurally related

a) Natural product is known to be active --> make changes in the compound to generate lead

b) If target is known + have a structure that is known ~ predict compounds that would bind computationally.

1) A metabolite may be the actual drug.

2) A second activity may be identified in clinical trials (good or bad)

3) A positive effect is discovered which can be a Lead for a new therapeutic.

UK921480 designed for hypertension and blocks activity of cGMP phosphodiesterase.

It inhibited that in the penis which led to more cGMP (high blood flow) so gives erections.

• 1. Identify the pharmacophore.
• 2. Identify the auxophore which could be "extra" or stabilizing/interfering with the pharmacophore.

By making derivatives + testing toward target.