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CONSIDERATION OF REACTION INTERMEDIATES IN STRUCTURE-ACTIVITY RELATIONSHIPS: A KEY TO UNDERSTANDING AND PREDICTION
Citation:
Richard, A M. AND P. Swartz. CONSIDERATION OF REACTION INTERMEDIATES IN STRUCTURE-ACTIVITY RELATIONSHIPS: A KEY TO UNDERSTANDING AND PREDICTION. Presented at 6th Int'l Symposium on Biological Reactive Intermediates: Session on Structure-Activity Relationships, Paris, France, 7/16-20/2000.
Description:
Consideration of Reaction Intermediates in Structure- Activity Relationships: A Key to Understanding and Prediction
A structure-activity relationship (SAR) represents an empirical means for generalizing chemical information relative to biological activity, and is frequently oriented towards the goal of predicting the activity of new chemicals. By virtue of its implicit relationship to the rate determining step of a biological interaction, however, an SAR can also serve as a valuable tool for inquiry into molecular mechanisms. Such efforts are guided and constrained by knowledge of likely biochemical activation pathways and chemical reactivity properties of structurally similar chemicals. It follows that information pertaining to biologically reactive intermediates and their formation is highly relevant to, and can be potentially inferred from mechanistically informative SAR models. There are many examples of SAR models where an empirical association has either revealed or been strengthened by explicit hypothesis or knowledge of chemical reaction intermediates. The use of molecular modeling and SAR concepts to complement and clarify experimental observation will be demonstrated in examples pertaining to glutathione-mediated bioactivation of haloalkenes and haloacids. In particular, an example involving modeling of GST -Zeta substrate selectivity and activity of a series of haloacids will illustrate how consistencies in relative biological activities and plausible chemical reaction scenarios have the potential to shed light on enzyme activation mechanisms.
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