Molecular modeling and in vitro reactivation study between the oxime BI-6 and acetylcholinesterase inhibited by different nerve agents

Abstract

Nerve agents are organophosphates acting as potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of acetylcholine and, consequently, the termination of the transmission of nerve impulses. The inhibition of AChE by an organophosphate can be reversed by a nucleophilic agent able to dephosphorylate a serine residue in the active site of AChE. In this sense, the oximes are compounds capable of removing the nerve agent and reactivate the enzyme. Here, we have applied a methodology involving theoretical docking and Quantum Mechanics/Molecular Mechanics, using the softwares Molegro^® and Spartan^®, to evaluate the kinetic constants of reactivation and the interactions of the oxime BI-6 with AChE inhibited by different organophosphorus compounds in comparison to in vitro data. Results confirm that this method is suitable for the prediction of kinetic and thermodynamic parameters of oximes, which may be useful in the design and selection of new and more effective oximes.

Keywords:

• chemical warfare
• organophosphates
• acetylcholinesterase
• QM/MM
• molecular docking
• oximes

Acknowledgments

The authors wish to thank the Brazilian financial agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (Grants 304557/2012-9 and 474757/2012-9), Fundação de Amparo ao Ensino e Pesquisa do Estado do Rio de Janeiro (FAPERJ) (Grant E-26/102.993/2012), Fundação de Amparo ao Ensino e Pesquisa de Minas Gerais (FAPEMIG) (Grant no PPM-00499-13, and PPM-00434-13) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ Ministério da Defesa (CAPES/MD) (Edital PRODEFESA 2008, grant no PD 1782/2008) for financial support, and the Military Institute of Engineering (IME) and Federal University of Lavras (UFLA) for providing the physical infrastructure and working space.

Additional information

Funding

This work was supported by MH CZ-DRO (FNHK). This work was also supported by Excellence project FIM.