Enzimologia computacional aplicada à degradação de agentes neurotóxicos organofosforados: cálculos de interação e mecanismo de reação

Abstract

The study of the reactivity and synthesis of phosphorus compounds began in the 19th century, after the discovery of some of their toxic properties. Since then, organophosphorus compounds (OP), also called neurotoxins or nerve agents, are used as chemical weapons. The toxicity of these compounds is due to the inhibition of acetylcholinesterase (AChE), the enzyme responsible for controlling the nerve impulses transmission. The action of neurotoxins as AChE inhibitors interrupts the hydrolysis of ACh, and may lead to an irreversible inhibition of this enzyme, resulting in the cholinergic syndrome. Some enzymes have been characterized with the potential to degrade OP. However, to date no universal agent for treatment has been found to be effective against all known compounds and their effects. In search for expanding the strategies of bioremediation, it was proposed to evaluate the potential of dUTPase enzyme in degrading nerve agents. The enzyme has become a strong candidate because it has a good potential to degrade phosphotriesters. Theoretical methodology of molecular docking, chemometrics and QM/MM was used in order to evaluate the interaction mode of dUTPase with the neurotoxic organophosphorus Sarin and VX, considering their enantiomers "Rp " and "S p ". The results demonstrate that the two proposed degradation mechanisms seem to be promising, especially with respect to the VX agent, in which the enzyme showed considerable stereoselectivity. This stands for a starting point to lead to a better understanding on the hydrolysis mechanism and reactivity of the enzyme. In this way, dUTPase is a good option to expand the range of neurotoxic agents that can be degraded.