No presente trabalho foi aplicada uma metodologia teórica desenvolvida em um trabalho anterior que utiliza os programas Molegro ® e Spartan ® para avaliar as constantes cinéticas de associação e reativação de oximas, em relação a resultados in vitro previamente reportados na literatura. Como observado antes, os resultados mostraram boa correlação entre as energias livres teóricas de ligação das oximas e os dados experimentais, corroborando a metodologia como adequada para a predição de parâmetros cinéticos e termodinâmicos, os quais podem ser úteis para o planejamento e seleção de novas e mais efetivas oximas.In this work we applied a theoretical methodology developed in a former work, using the Molegro ® and Spartan ® softwares, to evaluate the association and kinetic reactivation constants of oximes, facing in vitro data previously reported in the literature. As reported before, results showed a good agreement between the theoretical binding free energies of the oximes and experimental data, corroborating the methodology as suitable for the prediction of kinetic and thermodynamic parameters that might be helpful for the design and selection of new and more effective oximes. Keywords: acetylcholinesterase, QM/MM, chemical mechanism of reactivation, neurotoxic agents IntroductionThe action of the nerve agents 1,2 as inhibitors of the enzyme acetylcholinesterase (AChE) stops the hydrolysis of the neurotransmitter acetylcholine and can lead to an irreversible inhibition of this enzyme (aging) thus triggering the cholinergic syndrome.3 To avoid this it's necessary a nucleophile, like an oxime, whose hydroxyl group is believed to be able to remove the nerve agent from the active site and reactivate AChE (Scheme 1). This reactivation reaction (illustrated in equation 1) involves, first, the association of the oxime to the inhibited enzyme (EIOx) and then the reactivation of the enzyme by the leaving of the oxime complexed to the neurotoxic agent (I-Ox).Where K R and k r are the dissociation constants, which represent the affinity of oximes for the inhibited AChE, and the rate constant for the decomposition of the stable enzyme-inhibitor-reactivator complex, respectively. 4,5The literature reports many structurally different oximes able to perform the reactivation of AChE inhibited by several different nerve agents, but one structure able to act efficiently against all the existing neurotoxic agents has not yet been reported 4,5 and oximes that are efficient against one specific nerve agent can be completely ineffective with another.2-6 Several molecular modelling studies available in literature point out to important features on the oximes structures that could be very useful to guide experimental research on this issue. [7][8][9][10][11][12][13][14][15][16][17][18][19] In a former work 4 we have Methodology Ligands data set and docking energy calculationsThe in vitro data of K R and k r for the oximes studied in this work (Figure 1) regarding AChE inhibited by cyclosarin, were reported by Kassa et al. 5 Crystallogr...
In order to contribute to a better understanding of the mechanism of action of oximes, we evaluated the affinities of 10 new oximes, derived from pyridine-imidazol bicycled systems, for human acetylcholinesterase (HssAChE) complexed with tabun, by estimating their docking energy values and comparing of the values obtained to known oximes using the software Molegro Virtual Docker (MVD) ®. We evaluated the influence of the position of the oxime group as substituent in the structures and, also, the influence of the oxime group syn-anti isomery on the docking score values for all the molecules studied. Results suggest that: the affinities of the 10 new oximes for the tabun inhibited HssAChE active site are better than pralidoxime's and similar to trimedoxime's; the meta-pralidoxime could have more affinity for the HssAChE active site and the oximes' anti isomers could present slightly better affinities for the HssAChE active site than the syn isomers.
We have applied a theoretical methodology, previously developed to evaluate the association and kinetic reactivation constants of oximes, comparing theoretical data obtained for human acetylcholinesterase (HsAChE) with in vitro results from Mus musculus AChE (MmAChE) previously reported in the literature. Our results, further checked by additional molecular dynamics simulations steps, showed a good correlation between the theoretical and experimental data, supporting the methodology as appropriate for prediction of thermodynamic and kinetic parameters and corroborated MmAChE as a suitable model for studies with HsAChE.
Hepatitis C virus (HCV) is a Hepacivirus that causes chronic liver disease, leading to hepatocellular carcinoma, cirrhosis, and chronic hepatitis in about 3% of the world population. In this study, novel HCV NS3 serine protease inhibitors based on 93 boceprevir analogs were studied by QSAR analyses using thermodynamic, structural and topological descriptors, including E-state descriptors. Novel compounds were proposed using the QSAR models. Both models were highly predictive, with calibration, leave-one-out validation and external validation R2 of 0.66, 0.65 and 0.52, respectively. The most promising structures were docked into the HCV NS3 serine protease active site demonstrating, then, the high affinity of some new structures.
Acetylcholinesterase (AChE) is responsible for hydrolysis of acetylcholine (ACh), a function, which if disrupted, leads to cholinergic syndrome. Carbamates (CB) and organophosphorus compounds (OP) are AChE inhibitors, toxic and capable of causing severe poisoning or death to exposed individuals. The AChE reactivation is considered the main function of the oximes. In case of poisoning by CB, there is no consistent data in the literature for an oxime reactivation mechanism. In this work, we evaluated the affinity and reactivity of oximes with activity already reported against AChE inhibited by the OP chemical warfare agent ciclosarin, with MmAChE and HsAChE active sites inhibited by the CB pesticide carbofuran. Thus, our theoretical data indicate that HLO-7, BI-6 and K005 compounds may be promising reactivators of AChE inhibited by carbofuran.
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