Quantum chemical calculations for understanding and predicting toxicity. I. Ab initioMODPOT/VRDDO calculations and electrostatic molecular potential contour maps of organophosphorus anticholinesterases

Abstract

To demonstrate the feasibility of quantum chemical and other theoretical techniques in the understanding and correlation and then in the prediction of toxicity of a specific class of compounds, the organophosphorus acetylcholinesterase (AChE) inhibitors were chosen since these have relatively clear-cut one-dose acute lethal toxicity, both LD50, and ED50 for the triggering event inhibition of AChE, to serve as well-defined end points. It was possible to identify particular quantum chemical requisites which are related to and predictive of the toxic effects of these molecules. Ab initio calculations were carried out on a number of organophosphorus compounds using our own programs which incorporate a number of desirable options for ab initio calculations on large molecules, including ab initio effective core model potentials (MODPOT), which permit calculations of valence electrons only explicitly, yet accurately, and a charge-conserving integral prescreening evaluation (which we named VRDDO—variable retention of diatomic differential overlap) especially effective for spatially extended molecules. Ab initio calculations were carried out for the two optical isomers of GB: These isomers differ in their toxicities. From the wavefunctions of the optical isomers of GB (calculated relative to internal body-fixed coordinates) the electrostatic molecular potential contour maps (relative to the same absolute space-fixed reference coordinates) were generated in three dimensions around each molecule. These maps indicate vividly the differing stereoelectronic requisites for the different optical isomers and suggest the basis for the difference in their in vivo toxicities. These maps form three-dimensional stereoelectronic holograms and can even be used for reverse image holography to ascertain if new even hypothetical molecules fulfill the requisites. This is related to the first step in the inhibition of AChE, complex formation of the organophosphorus compound with AChE.