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MOLECULAR INTERACTION POTENTIALS FOR THE DEVELOPMENT OF STRUCTURE-ACTIVITY RELATIONSHIPS
Citation:
Rabinowitz, J. R., S. B. Little, AND E. M. Gifford. MOLECULAR INTERACTION POTENTIALS FOR THE DEVELOPMENT OF STRUCTURE-ACTIVITY RELATIONSHIPS. Chapter 7, John D. Walker, Ph.D. (ed.), QSARs for Pollution Prevention, Toxicity Screening, Risk Assessment, and Web Development. SETAC Press, Pensacola, FL, (1998).
Description:
Abstract
One reasonable approach to the analysis of the relationships between molecular structure and toxic activity is through the investigation of the forces and intermolecular interactions responsible for chemical toxicity. The interaction between the xenobiotic and the biomolecular target for its activity is often the differential step in the mechanism of activity. For mechanisms in which the target molecule is unknown, molecular interaction potentials may be used to identify the salient features of that interaction. The molecular electrostatic and steric potentials have been used for these purposes. These potentials omit a potentially important part of the intermolecular interaction, that is, the effect
the interaction has on the electronic structure of the interacting molecules. These effects may be included in a more complete potential. A potential of this type was computed for a series of dioxins. Results obtained with this potential were qualitatively different from those obtained with the molecular electrostatic potential for 2,3,7,8-tetrachloro-dioxin. In the complete potential, there is a region above the oxygen atoms that is attractive for positive charge. In the molecular electrostatic potential for the same molecule, that region is repulsive.
The induced dipole moment of the p-system of these molecules plays a major role in this interaction. These dipoles are not considered by the electrostatic potential. The implication of these results for structure-activity analysis is considered. In addition, the differences in the requirements of a structure-activity relationship for drug design and environmental assessment are discussed.