Molecular modeling and in vitro reactivation study between the oxime BI-6 and acetylcholinesterase inhibited by different nerve agents |
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| Authors: | Juliana OS Giacoppo Tanos CC França Kamil Kuča Elaine FF da Cunha Ruben Abagyan Daiana T Mancini |
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| Institution: | 1. Laboratory of Molecular Modeling, Chemistry Department, Federal University of Lavras, Lavras, MG, Brazil;2. Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense (LMCBD), Military Institute of Engineering, Rio de Janeiro, RJ, Brazil;3. Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, Hradec Kralove, Czech Republic;4. Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, Hradec Kralove, Czech Republic;5. Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic;6. Skaggs School of Pharmacy &7. Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA, USA |
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| 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. |
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| Keywords: | chemical warfare organophosphates acetylcholinesterase QM/MM molecular docking oximes |
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