Overview: The Search for Biologically Useful Chemical Space

The search for and use of biologically active chemicals by man dates to the dawn of Homo sapiens and to his ancestors. Although the paradigm of drug discovery has changed significantly in the past several decades through the introduction of genomics, combinatorial chemistry, and high-throughput screening, the fundamental challenges remain unchanged—these are the identification and validation of targets for drug action and the discovery of biologically active molecules. This chapter is concerned primarily with the issues surrounding the exploration of chemical space, including the relationship between chemical and biological space, stereoselectivity of drug interaction, privileged structures, structure–function relationships, selectivity and nonselectivity of drug action, and the elucidation of biological space through X-ray crystallography. The amount of chemical space mapped by biologically active compounds is extremely small. Confirmation of this for small molecule ligands that represent the dominant fraction of therapeutically available drugs is provided by an analysis of the structural properties of known drugs.