RESUMEN
In the present work, we performed a complementary quantum mechanical (QM) study to describe the mechanism by which deprotonated pralidoxime (2-PAM) could reactivate human (Homo sapiens sapiens) acetylcholinesterase (HssAChE) inhibited by the nerve agent VX. Such a reaction is proposed to occur in subsequent addition-elimination steps, starting with a nucleophile bimolecular substitution (SN2) mechanism through the formation of a trigonal bipyramidal transition state (TS). A near attack conformation (NAC), obtained in a former study using molecular mechanics (MM) calculations, was taken as a starting point for this project, where we described the possible formation of the TS. Together, this combined QM/MM study on AChE reactivation shows the feasibility of the reactivation occurring via attack of the deprotonated form of 2-PAM against the Ser203-VX adduct of HssAChE.
Asunto(s)
Acetilcolinesterasa/efectos de los fármacos , Compuestos Organotiofosforados/farmacología , Compuestos de Pralidoxima/farmacología , Acetilcolinesterasa/química , Dominio Catalítico , Humanos , Conformación Molecular , Simulación de Dinámica Molecular , Compuestos de Pralidoxima/química , Protones , Teoría Cuántica , Serina/químicaRESUMEN
7-methoxytacrine-4-pyridinealdoxime (7-MEOTA-4-PA, named hybrid 5C) is a compound formerly synthesized and evaluated in vitro, together with 4-pyridine aldoxime (4-PA) and commercial reactivators of acetylcholinesterase (AChE). This compound was designed with the purpose of being a prophylactic reactivator, capable of interacting with different subdomains of the active site of AChE. To investigate these interactions, theoretical results from docking were first compared with experimental data of hybrid 5C, 4-PA, and two commercial oximes, on the reactivation of human AChE (HssAChE) inhibited by VX. Then, further docking studies, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area calculations, were carried out to investigate reactivation performances, considering the near attack conformation (NAC) approach, prior to the nucleophilic substitution mechanism. Our results helped to elucidate the interactions of such molecules with the different subdomains of the active site of HssAChE. Additionally, NAC poses of each oxime were suggested for further theoretical studies on the reactivation reaction.
Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Cloruro de Obidoxima/farmacología , Compuestos Organotiofosforados/farmacología , Oximas/farmacología , Compuestos de Pralidoxima/farmacología , Piridinas/farmacología , Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Cloruro de Obidoxima/química , Compuestos Organotiofosforados/química , Oximas/química , Compuestos de Pralidoxima/química , Piridinas/química , Relación Estructura-ActividadRESUMEN
Tabun is one of the most dangerous nerve agents because it has deleterious effects like inhibition of the essential enzymes acetylcholinesterase (AChE) and butyrylcholinesterase. Some oximes such HI6 as 2-PAM are nucleophiles that are capable to reactivate inhibited human AChE under some conditions. Zwitterionic and cationic species have the best chance of productive action on inhibited AChE. However uncharged oximes can give important interaction information. In order to investigate the interaction and behavior of cationic and uncharged oximes, we performed molecular docking simulations and molecular dynamics and calculated binding energies of complexes of these compounds with human AChE. The uncharged oximes of larger structure were more susceptible to the influence of the substituents on the phosphorus atom and presented low binding energies. In contrast, HI 6 and 2-PAM showed high binding energy values with great contribution of the amino acid Asp74, demonstrating the importance of the quaternary nitrogen to the affinity and interaction of the oximes/AChE tabun-inhibited complexes.
Asunto(s)
Acetilcolinesterasa/química , Inhibidores de la Colinesterasa/química , Reactivadores de la Colinesterasa/química , Organofosfatos/química , Oximas/química , Compuestos de Pralidoxima/química , Humanos , Simulación del Acoplamiento Molecular/métodosRESUMEN
The present work describes a simple integrated Quantum Mechanics/Molecular Mechanics method developed to study the reactivation steps by pralidoxime (2-PAM) of acetylcholinesterase (AChE) inhibited by the neurotoxic agent Tabun. The method was tested on an AChE model and showed to be able to corroborate most of the results obtained before, through a more complex and time-consuming methodology, proving to be suitable to this kind of mechanistic study at a lower computational cost.