Structure and mode of action of organophosphate pesticides: A computational study

Abstract

Six organophosphate pesticides of high to moderate toxicity (dichlorvos (DCV), dicrotophos (DTP), ethoprophos (EPP), methamidophos (MAP), mevinphos (MVP) and omethoate (OMT)) are computationally studied to determine their structure and up to 12 different mechanisms of reaction with methanol. Methanol is chosen as a surrogate molecule to represent the serine residue and imidazole to represent histidine in the active site of acetylcholinesterase, the target enzyme in the central nervous system of organisms. Transition states (first order saddle points) and intermediates along several plausible reaction pathways are computed, along with activation enthalpies, entropies, and free energies. Pathways for different leaving groups are also analyzed. All geometry optimizations of products, reactants, intermediate complexes, and saddle points were performed using hybrid density functional theory method mPW1B95-44 in conjunction with the 6-31+G(d,p) basis set, with and without a polarized continuum model of implicit solvation. Composite rate constants were calculated using a steady-state analysis for mechanisms with more than one activation barrier. Mechanisms explored fall into two main categories, direct and indirect, all involving proton transfer from the methanol hydroxyl group to the oxygen or sulfur of the leaving group. The indirect proton-transfer mechanism is a Wright-type mechanism (Wright and White, 1998) which relays the proton through the phosphinyl oxygen, and the leaving group is positioned on the opposite side to the incoming hydroxyl nucleophile in a distorted trigonal bipyramidal transition state. We explored mechanisms in which one or two water molecules and/or an imidazole molecule assisted in the proton transfer. Generally speaking, whether direct or indirect, the lowest activation energies were obtained for mechanisms in which the phosphinyl oxygen plays a role in transfer, and additionally water assistance (ubiquitous in the enzyme active site) lowers activation barriers.