Conformational Analysis of Environmental Agents: Use of X-Ray Crystallographic Data to Determine Molecular Reactivity

Abstract

This paper explores the use of crystallographic techniques as an aid in understanding the molecular reactivities of a number of agents that are of concern to pharmacologists and toxicologists. The selected examples demonstrate the role of structural data in the determination of absolute configuration, configurational flexibility and active-site topology for a reactive species. For example, the role of absolute stereochemistry in understanding synthetic pyrethroid structure-activity relationships is shown from analysis of their crystal structures; conformational flexibility among DDT analogues, and the importance of conformational and electronic properties in phenylalkanoic acid herbicides are shown from systematic analysis of their crystal structures; and interpretation of active-site stereochemistry is made by study of computer modeling of enzyme inhibitors in the active sites of related protein crystal structures. Thus, the observed patterns in conformational flexibility and their resultant effects on substrate pharmacological profile can be interpreted in understanding the molecular level events that influence biological reactivity.

Interactions of halogenated industrial chemicals with transthyretin and effects on thyroid hormone levels in vivo

“…2), Additional industrial chemicals such as chlorophenoxy acids (Table 1, group 2) and nitrophenols (Table 1, group 3) were also effective competitors for the T4 binding site. Theoretical modelling studies by Cody (1985) have suggested potential fitting of chlorophenoxy acids in the binding pocket of transthyretin. Little is known about in vivo effects of chlorophenoxy acids and nitrophenols with respect to thyroid hormone levels in man or experimental animals.…”

“…Modelling studies also indicate a fit of DDT in the T4 binding pocket of transthyretin (Cody 1985). The thyroid hormone-lowering effect of DDT, the parent compound, in a few experimental animals systems is well known (Bastomski 1974;Hurst et al 1974).…”