Quantum Chemical and Theoretical Investigations of Toxicity

摘要

The objective of the present research is to demonstrate the feasibility of quantum chemical and other theoretical techniques in the correlation and then in the prediction of toxicity of a specific class of compounds. The family of compounds we chose were the organophosphorus pesticides and nerve gases, since both have relatively clearcut one-dose acute lethal toxicity, LD50, and ED50 for the triggering event, inhibition of acetylcholinesterase, to serve as well-defined end points. The first year we carried out ab-initio calculations on a number of phosphorus compounds, including the two optical isomers of GB. From the wave functions of the optical isomers of GB we generated the electrostatic molecular potential contour maps in three dimensions around each molecule and the computer displayed a few of them as two-dimensional planes. Even the two-dimensional maps indicated vividly the differing stereoelectronic requisites for the different optical isomers and suggested the basis for the differences in their in-vivo toxicities. This past year we have written programs which created and displayed computer images of these maps in three dimensions. These three-dimensional maps indicate differing stereoelectronic requisites for interaction of biological molecules with enzyme active sites and with receptor sites. We are initiating research on how best to computer match these maps in multidimensional space. This is related to the first step in the inhibition of AChE.