Lead Generation

In the drug discovery process, a promising compound is referred to as a lead. The lead is a compound that demonstrates some desirable therapeutic or pharmacological characteristics, but at the same time, it may also show some undesirable effects like toxicity or poor absorption. Medicinal chemists use multiple techniques to identify leads that could be suitable for molecular modification in order to amplify the desirable characteristics and to eliminate, or minimize to an acceptable level, the undesirable characteristics. When the lead compound has been properly modified to get all the desirable characteristics of an active therapeutic agent, it then becomes a drug candidate. This entire process is referred to as lead generation.

There have been a few exceptional cases in which a pharmacologically active substance has been discovered without lead generation. One such example is the discovery of penicillin.

Alexander Fleming discovered penicillin in 1928. After inadvertently leaving a culture dish of Staphylococcus aureus on the lab bench during his vacation, he noticed bacteriolytic properties of a mold contaminating the dish. The mold was found to be a Penicillium strain. After the structure was fully elucidated by X-ray crystallography, penicillin itself became a lead and medicinal chemists modified the structure to improve its pharmacological activity. They substituted different chemical groups and they managed to synthesize different analogs (called second-generation analogs), which offered additional desirable characteristics. Some of these penicillin analogs are still in use (Penicillin V and Penicillin G).

We cannot really count on serendipity to discover new leads in modern medicinal chemistry, and a whole battery of tools has been developed to help identify new and promising compounds. One major obstacle in lead generation is how to discriminate among hundreds of different compounds in order to find the one that has the most potential. Researchers utilize different screens or assays in order to do this. In vitro assays (outside of the organism) are faster and less expensive to perform. These kinds of tests are often roboticized and can therefore be performed very quickly with many different leads.

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