Organophosphorus compound esterase profiles as predictors of therapeutic and toxic effects

Махаева, Галина Ф.; Radchenko, Eugene V.; Palyulin, V. A.; Рудакова, Е. В.; Aksinenko, А. Yu.; Соколов, В. Б.; Зефиров, Н. С.; Richardson, Rudy J.

doi:10.1016/j.cbi.2012.10.012

Cited by 66 publications

(26 citation statements)

References 31 publications

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“…We used human erythrocyte AChE, equine serum BChE, and porcine liver CaE. It was shown previously that the two last-mentioned enzymes have a high identity to the human enzymes4041. The inhibitory activity was characterized as the percentage of inhibition at 20 μM or as the IC 50 value, i.e., the inhibitor concentration required to reduce the enzyme activity by 50%.…”

Section: Resultsmentioning

confidence: 99%

Novel conjugates of aminoadamantanes with carbazole derivatives as potential multitarget agents for AD treatment

Бачурин¹,

Shevtsova²,

Махаева³

et al. 2017

Sci Rep

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A new group of compounds, promising for the design of original multitarget therapeutic agents for treating neurodegenerative diseases, based on conjugates of aminoadamantane and carbazole derivatives was synthesized and investigated. Compounds of these series were found to interact with a group of targets that play an important role in the development of this type of diseases. First of all, these compounds selectively inhibit butyrylcholinesterase, block NMDA receptors containing NR2B subunits while maintaining the properties of MK-801 binding site blockers, exert microtubules stabilizing properties, and possess the ability to protect nerve cells from death at the calcium overload conditions. The leading compound C-2h has been shown the most promising effects on all analyzed parameters. Thus, these compounds can be regarded as promising candidates for the design of multi-target disease-modifying drugs for treatment of AD and/or similar neuropathologies.

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Section: Resultsmentioning

confidence: 99%

Novel conjugates of aminoadamantanes with carbazole derivatives as potential multitarget agents for AD treatment

Бачурин¹,

Shevtsova²,

Махаева³

et al. 2017

Sci Rep

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“…These in vitro findings confirm and extend previous work using mouse brain homogenates (Quistad et al ., 2002), hen or human brain homogenates (Capodicasa et al ., 1991; Emerick et al ., 2012; Lotti and Johnson, 1978; Richardson et al ., 1993) hen brain particulate fractions (Makhaeva et al ., 2013; Malygin et al ., 2003; Sogorb et al ., 2010) or preparations from human or murine cell cultures (Ehrich et al ., 1997; Li and Casida, 1997; Sogorb et al ., 2010). In addition, the present work provides new in vitro and in vivo data on the neuropathic potential of PrDChVP and two new compounds, diEt-PFP and diBu-PFP.…”

Section: Discussionmentioning

confidence: 99%

Further studies toward a mouse model for biochemical assessment of neuropathic potential of organophosphorus compounds

Махаева

Рудакова

Hein

et al. 2014

J of Applied Toxicology

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Inhibition and aging of neuropathy target esterase (NTE) by neuropathic organophosphorus (OP) compounds triggers OP compound-induced delayed neuropathy (OPIDN), whereas inhibition of acetylcholinesterase (AChE) produces cholinergic toxicity. The neuropathic potential of an OP compound is defined by its relative inhibitory potency (RIP) toward NTE vs. AChE assessed by enzyme assays following dosing in vivo or after incubations of direct-acting compounds or active metabolites with enzymes in vitro. The standard animal model of OPIDN is the adult hen, but its large size and high husbandry costs make this species a burdensome model for assessing neuropathic potential. Although the mouse does not readily exhibit clinical signs of OPIDN, it displays axonal lesions and expresses brain AChE and NTE. Therefore, the present research was performed as a further test of the hypothesis that inhibition of mouse brain AChE and NTE could be used to assess neuropathic potential using mouse brain preparations in vitro or employing mouse brain assays following dosing of OP compounds in vivo. Excellent correlations were obtained for inhibition kinetics in vitro of mouse brain enzymes versus hen brain and human recombinant enzymes. Furthermore, inhibition of mouse brain AChE and NTE after dosing with OP compounds afforded ED50 ratios that agreed with RIPs assessed in vitro. Taken together, results with mouse brain enzymes demonstrated consistent correspondence between in vitro and in vivo predictors of neuropathic potential, thus adding to previous studies supporting the validity of a mouse model for biochemical assessment of the ability of OP compounds to produce OPIDN.

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“…45–51 This is because BChE has a large active site gorge (~200 Å 3 ) and its inhibitors possess diversity of size/structures, which results in the difficulty to build a reasonable QSAR model with satisfied quality. With the previous twenty-five descriptors selected by the stepwise regression procedure for building the MLR model, in this study the back propagation neural network model with architecture NN10-h-1 (h=1 to 3) was trained and leave-one/n-out validated, in which 10 is the number of input neurons corresponding to the ten descriptors, and h represents the number of hidden neurons.…”

Section: Resultsmentioning

confidence: 99%

Modeling in vitro inhibition of butyrylcholinesterase using molecular docking, multi-linear regression and artificial neural network approaches

Zheng

Zhan

Huang

et al. 2014

Bioorganic & Medicinal Chemistry

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Butyrylcholinesterase (BChE) has been an important protein used for development of anti-cocaine medication. Through computational design, BChE mutants with ~2000-fold improved catalytic efficiency against cocaine have been discovered in our lab. To study drug-enzyme interaction it is important to build mathematical model to predict molecular inhibitory activity against BChE. This report presents a neural network (NN) QSAR study, compared with multi-linear regression (MLR) and molecular docking, on a set of 93 small molecules that act as inhibitors of BChE by use of the inhibitory activities (pIC50 values) of the molecules as target values. The statistical results for the linear model built from docking generated energy descriptors were: r2 = 0.67, rmsd = 0.87, q2 = 0.65 and loormsd = 0.90; The statistical results for the ligand-based MLR model were: r2 = 0.89, rmsd = 0.51, q2 = 0.85 and loormsd = 0.58; the statistical results for the ligand-based NN model were the best: r2 = 0.95, rmsd = 0.33, q2 = 0.90 and loormsd = 0.48, demonstrating that the NN is powerful in analysis of a set of complicated data. As BChE is also an established drug target to develop new treatment for Alzheimer’s disease (AD). The developped QSAR models provide tools for rationalizing identification of potential BChE inhibitors or selection of compounds for synthesis in the discovery of novel effective inhibitors of BChE in the future.

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Organophosphorus compound esterase profiles as predictors of therapeutic and toxic effects

Cited by 66 publications

References 31 publications

Novel conjugates of aminoadamantanes with carbazole derivatives as potential multitarget agents for AD treatment

Novel conjugates of aminoadamantanes with carbazole derivatives as potential multitarget agents for AD treatment

Further studies toward a mouse model for biochemical assessment of neuropathic potential of organophosphorus compounds

Modeling in vitro inhibition of butyrylcholinesterase using molecular docking, multi-linear regression and artificial neural network approaches

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