W0124

Molecular Approaches to Drug Design. Judith L. Flippen-Anderson, Jeffrey R. Deschamps, and Clifford George, Laboratory for the Structure of Matter, Code 6030, Naval Research Laboratory, Washington, DC 20375.

The history of opium predates the written word. Nicotine, the most addictive drug available without prescription, is estimated to have contributed to the loss of 400,000 lives in the United States alone in 1988. More recent surveys indicate that there are nearly 400,000 people in the US using cocaine on a daily basis with 5,000 new users being added every day. The number of heroin users was estimated at more than 900,000 in 1999 with alarming increases in usage by suburban teens. Billions of dollars are spent every year in the "war" against these drugs. Ironically, many of these controlled substances can provide release from intense pain. Control of these drugs lies in being able to modify their properties, removing those that cause addiction while retaining, or even improving, those properties that provide analgesia. To do this we must understand their chemistry and biological activity. The key to this understanding is hidden in the structures of these compounds, the ligands, and in the structures of their receptors. If we can relate elements of structure to chemical and biological properties we can begin to design new compounds that can be used to treat drug abuse and to provide nearly complete pain relief without addiction. The three-dimensional information provided by x-ray crystallography, combined with computational methods can greatly enhance the discovery of new compounds and can efficiently optimize their properties. This presentation will focus on the x-ray structures of non-peptide ligands with the aim of relating structure to function.