Molecular Docking, Metal Substitution and Hydrolysis Reaction of Chiral Substrates of Phosphotriesterase

Title:Molecular Docking, Metal Substitution and Hydrolysis Reaction of Chiral Substrates of Phosphotriesterase

Volume: 19 Issue: 4

Author(s): Alexandre A. de Castro, Melissa S. Caetano, Telles C. Silva, Daiana T. Mancini, Eduardo Pereira Rocha, Elaine F.F. da Cunha and Teodorico C. Ramalho

Affiliation:

Keywords: Enzyme, Phosphotriesterase, QM/MM, MD, Organophosphorus.

Abstract: During World War II, organophosphorus compounds with neurotoxic action were developed and used as the basis for the development of structures currently used as pesticides in the agricultural industry. Among the nerve agents, Tabun, Sarin, Soman and VX are the most important. The factor responsible for the high toxicity of organophosphorus (OP) is the acetylcholinesterase inhibition. However, one of the characterized enzymes capable of degrading OP is Phosphotriesterase (PTE). This enzyme has generated considerable interest for applications of rapid and complete detoxification. Due to the importance of bioremediation methods for the poisoning caused by OP, this work aims to study the interaction mode between the PTE enzyme and organophosphorus compounds, in this case, Sarin, Soman, Tabun and VX have been used, which are potent acetylcholinesterase inhibitors, taking into account the enantiomers "R_p" and " S_p" of each compound, with the S_p-enantiomers presenting the higher toxicity. With that, we were able to demonstrate the existence of the stereochemical preference by PTE in these compounds. With the purpose of increasing the speed of the hydrolysis mechanism, we have proposed a modification in the enzyme active site structure, where Zn²⁺ ions were substituted by Al³⁺ ions. To analyze the stability of Al³⁺ ions in the wild-type PTE active site, MD simulations were also performed. This mutation brought relevant results; in this case, there was a reduction of the reaction energy barrier for all the compounds, mainly for VX in which the reaction presented lower activation energy values, and consequently, a faster hydrolysis process.

Cite this article as:

A. de Castro Alexandre, S. Caetano Melissa, C. Silva Telles, T. Mancini Daiana, Pereira Rocha Eduardo, F.F. da Cunha Elaine and C. Ramalho Teodorico, Molecular Docking, Metal Substitution and Hydrolysis Reaction of Chiral Substrates of Phosphotriesterase, Combinatorial Chemistry & High Throughput Screening 2016; 19 (4) . https://dx.doi.org/10.2174/1386207319666160325113844