Strategy for computer‐generated theoretical and quantum chemical prediction of toxicity and toxicology (and pharmacology in general)

Theoretical and quantum chemical prediction of toxicity and toxicology is even more challenging than prediction of pharmacology, which is usually a one‐stage event at a target site. For toxicity and toxicology, the concept of the “toxic triggering event” was developed which then leads to the cascade of subsequent physiological events. The strategy for computer‐generated predictions in this area includes as the major components chemical automated substructure and “toxicophore” identification by powerful chemical substructure searching techniques developed in Europe, geometry optimizations (desirably by ab‐initio intramolecular atom class‐atom class pair‐pair and three‐body potentials), quantum chemical calculations (desirably ab‐initio , incorporating optimal strategies for such computations on large molecules) on both the toxicant and its metabolites (the structures of which were generated by computer‐assisted tracing of metabolic pathways), generation of the three‐dimensional electrostatic molecular potential contour maps around the toxicants and their metabolites and matching of these by reverse image holography for new compounds whose toxicity has not yet been tested experimentally against those with a known toxic mechanism, matching of intermolecular interaction maps of untested compounds with known toxicants combined with matching observed physiologic signs and symptoms with “toxic triggering events” and specific pathologies, and using the concepts of systems analysis and control theory and catastrophe theory to track both the dynamic balance of endogenous biomolecules and interactions with these biomolecules. The necessary program modules are described, and the necessary data bases (both theoretical and physiological) are identified along with the form in which they may be used most expeditiously.