It is necessary to have a quick assay for the desired biological activity and to be able to separate the bioactive compound from the other inactive substances Lastly, a structural determination will need to be made

Finding the Lead (cont.) Screening synthetic banks Pharmaceutical companies have prepared thousands of compounds These are stored (in the freezer!), cataloged and screened on new targets as these new targets are identified

Finding the Lead (cont.) Using Someone Else’s Lead Design structure which is similar to existing lead, but different enough to avoid patent restrictions. Sometimes this can lead to dramatic improvements in biological activity and pharmacokinetic profile. (e.g. modern penicillins are much better drugs than original discovery).

Finding the Lead (cont.) Enhance a side effect

Use structural similarity to a natural ligand

Finding the Lead (cont.) Computer-Assisted Drug Design If one knows the precise molecular structure of the target (enzyme or receptor), then one can use a computer to design a perfectly-fitting ligand. Drawbacks: Most commercially available programs do not allow conformational movement in the target (as the ligand is being designed and/or docked into the active site). Thus, most programs are somewhat inaccurate representations of reality.

Finding a Lead (cont.) Serendipity: a chance occurrence Must be accompanied by an experimentalist who understands the “big picture” (and is not solely focused on his/her immediate research goal), who has an open mind toward unexpected results, and who has the ability to use deductive logic in the explanation of such results. Example: Penicillin discovery Example: development of Viagra to treat erectile dysfunction

Finding a Lead (cont.) Sildenafil (compound UK-92,480) was synthesized by a group of pharmaceutical chemists working at Pfizer's Sandwich, Kent research facility in England. It was initially studied for use in hypertension (high blood pressure) and angina pectoris (a form of ischaemic cardiovascular disease). Phase I clinical trials under the direction of Ian Osterloh suggested that the drug had little effect on angina, but that it could induce marked penile erections.

Pfizer therefore decided to market it for erectile dysfunction, rather than for angina. The drug was patented in 1996, approved for use in erectile dysfunction by the Food and Drug Administration on March 27, 1998, becoming the first pill approved to treat erectile dysfunction in the United States, and offered for sale in the United States later that year. It soon became a great success: annual sales of Viagra in the period 1999–2001 exceeded $1 billion.

Finding a Lead (cont.)