title: 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.
authors.affiliation: a Laboratory of Molecular Modeling, Chemistry Department , Federal University of Lavras , Lavras , MG , Brazil.
authors.forename: Juliana O S
authors.initials: JO
authors.lastname: Giacoppo
authors.forename: Tanos
authors.initials: T
authors.lastname: C C França
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuča
authors.forename: Elaine F F
authors.initials: EF
authors.lastname: da Cunha
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.forename: Daiana T
authors.initials: DT
authors.lastname: Mancini
authors.forename: Teodorico C
authors.initials: TC
authors.lastname: Ramalho
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D002801:Cholinesterase Reactivators / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D000067397:Nerve Agents / Q000737:chemistry* / Q000494:pharmacology; D010755:Organophosphates / Q000737:chemistry; D010091:Oximes / Q000737:chemistry* / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: C118647:BI 6; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D000067397:Nerve Agents; D010755:Organophosphates; D010091:Oximes; D011726:Pyridinium Compounds; D000110:Acetylcholinesterase
keywords: QM/MM; acetylcholinesterase; chemical warfare; molecular docking; organophosphates; oximes