Molecular Modeling in the Discovery of Drug Leads

The National Cancer Institute of the U.S.A. maintains a repository of about 500,000 chemicals which it has tested at some time for anticancer activity. As new chemotherapeutic targets present themselves, methods have been developed by which this large database can be re-examined without resorting to expensive high-volume biological screening. Electronic screening, the method described in this paper, begins with the identification of a target enzyme. The pharmacophore used by the enzyme in binding to substrates is identified, and then all compounds in the database that contain the pharmacophore are found. These compounds are then further filtered, for example, by physical properties such as solubility, and the relatively small number of compounds that survive are submitted for biological testing. This use of a primary electronic screen in the search for ligands of protein kinase C is described. The screen is very fast, and the method is quite generally applicable to different enzymes.