STRUCTURE ACTIVITY RELATIONSHIPS

A structure-activity relationship (SAR) is used to determine the primary, secondary, and tertiary structure of chemicals as a means of ascertaining the relationship between the effects of different compounds on biological systems. The history of SARs is over 150 years old and goes back to the laboratory of Louis Lewin, who, in the nineteenth century, developed the early chlorinated methane derivatives chloroform, carbon tetrachloride, and dichloromethane. The many derivatives of benzene (toluene, xylene, and others) also fall into this category. Once the organic chemists and medicinal chemists began to understand the impact of chemical structure on biological systems, the rudimentary basis of SARs commenced. By the 1920s, the chemistry of disinfectants, pesticides, and some drugs was based on SAR.

A classic example of an early SAR was the discovery of the benefits of acetylsalicylic acid (aspirin) and its near congeners, acetaminophen and salicylate. Another early classic example of a SAR was the development of DDT and its analogs and congeners. Several organochlorine pesticides are members of this broad family. The organophosphate insecticides are derivatives of the nerve gases. They were structurally engineered to be less toxic than nerve gases but to work by the same basic mechanism.

Modern SAR analysis is used to develop almost all drugs. Once the prototype drug is discovered and its three-dimensional characteristics determined, the chemists and structural biologists can then use the SAR to better understand the interaction between the drug and the affected protein or membrane.

The role of the SAR in public health has evolved in a manner similar to drugs. Based on seminal work carried out by many investigative teams, the key structural determinants of a large class of toxicants have been identified. For example, many of the determinants of carcinogenic activity have been characterized and published. Investigators can then use the SAR to examine a novel chemical structure to see if it contains one or more of the determinants of carcinogenicity. The ability to use SARs allows for a tier approach to carcinogenicity testing. The mutagenic potential of several classes of chemicals has also been cataloged to the extent that SARs can be used to examine novel molecules. There is a developing database to use SARs for the determination of skin and eye irritants. In each of these cases the effective use of SARs saves time, resources, and animals. As new and better methods of determining the three-dimensional structure of genes and proteins become available, the importance of SARs for toxicology will be critical. Coupling SARs with gene and protein structure should allow the investigator to determine the exact site of action of a toxicant. Understanding the function of any given gene (functional genomics) or protein (functional proteomics) can then be used to determine toxicity and risk.

Michael Gallo

(see also: Carcinogen Assessment Groups; Carcinogenesis; Toxicology )