Role of computational chemistry in support of hazard identification (ID): mechanism-based SARs

Abstract

A mechanism-based structure-activity relationship (SAR) study examines the structural basis for a chemical/biological activity by targeting a single or a few stages in a postulated mechanism of action. Computational chemistry approaches provide a valuable complement to experiment for probing such associations, but require a highly focused viewpoint that neglects much of the full biological and chemical interaction problem. Research questions are formulated in terms of fundamental structure and reactivity properties and are designed to test key assumptions of a postulated mechanism of activity. The results of such studies can aid in the generation of new hypotheses, suggest new experiments, and provide scientific rationale for extrapolation in hazard identification (ID). Toxicologists and computational chemists bring very different, yet complementary viewpoints, approaches, and expertise to bear on the hazard ID problem. However, improved communication and interaction between these two groups is needed to most productively address hazard ID issues.