High throughput screening (HTS)
~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.
Things to consider about drug screening
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 --> Viagra
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.
Determining the pharmacophore
By making derivatives + testing toward target.
HTS, rational design, Viagra