The key role of butyrylcholinesterase during neurogenesis and neural disorders: an antisense-5′butyrylcholinesterase-DNA study

Mack, Alexandra; Robitzki, Andrea A.

doi:10.1016/s0301-0082(99)00047-7

Cited by 128 publications

(65 citation statements)

References 69 publications

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“…On the other hand, it has been known that BChE is overexpressed in patients with Alzheimer's disease (Guillozet et al, 1997) and the presence of BChE with ␤-amyloid plaques dramatically amplifies the toxicity of ␤-amyloid (Barber et al, 1996). In addition, increased BChE gene expression correlates with neurodegenerative disorders (Mack and Robitzki, 2000). In light of these published reports, without further studies, we do not know for sure that the administration of a BChE mutant with significantly increased activity against ACh will not cause any unexpected adverse effects for the patients, particularly those who also suffer from Alzheimer's disease or other neurodegenerative disorders.…”

Section: Discussionmentioning

confidence: 95%

Design, Preparation, and Characterization of High-Activity Mutants of Human Butyrylcholinesterase Specific for Detoxification of Cocaine

Xue¹,

Ko²,

Tang³

et al. 2010

Mol Pharmacol

104

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Cocaine is a widely abused drug without a U.S. Food and Drug Administration-approved medication. There is a recognized, promising anticocaine medication to accelerate cocaine metabolism, producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway [i.e., cocaine hydrolysis catalyzed by butyrylcholinesterase (BChE) in plasma]. An ideal, therapeutically valuable mutant of human BChE should have not only a significantly improved catalytic activity against (Ϫ)-cocaine but also certain selectivity for (Ϫ)-cocaine over neurotransmitter acetylcholine (ACh), such that one would not expect systemic administration of the BChE mutant to interrupt cholinergic transmission. The present study accounting for the mutation-caused changes of the catalytic activities of BChE against both (Ϫ)-cocaine and ACh by means of molecular modeling and site-directed mutagenesis has led to identification of three BChE mutants that have not only a considerably improved catalytic efficiency against (Ϫ)-cocaine but also the desirable selectivity for (Ϫ)-cocaine over ACh. Two representative BChE mutants have been confirmed to be potent in actual protection of mice from acute toxicity (convulsion and lethality) of a lethal dose of cocaine (180 mg/kg). Pretreatment with the BChE mutant (i.e., 1 min before cocaine administration) dose-dependently protected mice against cocaineinduced convulsions and lethality. In particular, all mice pretreated with the mutant (e.g., 0.02 mg or more of A199S/F227A/S287G/ A328W/E441D BChE) survived. The in vivo data reveal the primary factor (i.e., the relative catalytic efficiency), determining the efficacy in practical protection of mice from the acute cocaine toxicity and future direction for further improving the efficacy of the enzyme in the cocaine overdose treatment.

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Section: Discussionmentioning

confidence: 95%

Design, Preparation, and Characterization of High-Activity Mutants of Human Butyrylcholinesterase Specific for Detoxification of Cocaine

Xue¹,

Ko²,

Tang³

et al. 2010

Mol Pharmacol

104

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“…Hence, in recent years, many scientists and researchers have shown keen interest in designing small molecules that can inhibit BChE activity [18][19][20][21][22][23] . However, there is also increasing evidence of BChE's involvement in non-cholinergic functions such as cell differentiation [24] , neurogenesis, and the formation of amyloid plaques in AD [25][26][27] . In this work, we used computer-aided drug design approaches to identify novel and potent inhibitors of BChE.…”

Section: Introductionmentioning

confidence: 99%

Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors

Sakkiah

Lee

2012

Acta Pharmacol Sin

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Aim: To identify the critical chemical features, with reliable geometric constraints, that contributes to the inhibition of butyrylcholinesterase (BChE) function. Methods: Ligand-based pharmacophore modeling was used to identify the critical chemical features of BChE inhibitors. The generated pharmacophore model was validated using various techniques, such as Fischer's randomization method, test set, and decoy set. The best pharmacophore model was used as a query in virtual screening to identify novel scaffolds that inhibit BChE. Compounds selected by the best hypothesis in the virtual screening were tested for drug-like properties, and molecular docking study was applied to determine the optimal orientation of the hit compounds in the BChE active site. To find the reactivity of the hit compounds, frontier orbital analysis was carried out using density functional theory. Results: Based on its correlation coefficient (0.96), root mean square (RMS) deviation (1.01), and total cost (105.72), the quantitative hypothesis Hypo1 consisting of 2 HBA, 1 Hy-Ali, and 1 Hy-Ar was selected as the best hypothesis. Thus, Hypo1 was used as a 3D query in virtual screening of the Maybridge and Chembridge databases. The hit compounds were filtered using ADMET, Lipinski's Rule of Five, and molecular docking to reduce the number of false positive results. Finally, 33 compounds were selected based on their critical interactions with the significant amino acids in BChE's active site. To confirm the inhibitors' potencies, the orbital energies, such as HOMO and LUMO, of the hit compounds and 7 training set compounds were calculated. Among the 33 hit compounds, 10 compounds with the highest HOMO values were selected, and this set was further culled to 5 compounds based on their energy gaps important for stability and energy transfer. From the overall results, 5 hit compounds were confirmed to be potential BChE inhibitors that satisfied all the pharmacophoric features in Hypo1. Conclusion: This study pinpoints important chemical features with geometric constraints that contribute to the inhibition of BChE activity. Five compounds are selected as the best hit BchE-inhibitory compounds.

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“…The physiological role of BChE remains unclair (11,12). Although it is capable of hydrolyzing ACh and other acylcholines, so far no endogenous natural substrate has been described for this enzyme.…”

mentioning

confidence: 99%

Crystal Structure of Human Butyrylcholinesterase and of Its Complexes with Substrate and Products

Nicolet

Lockridge

Masson

et al. 2003

Journal of Biological Chemistry

720

572

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Cholinesterases are among the most efficient enzymes known. They are divided into two groups: acetylcholinesterase, involved in the hydrolysis of the neurotransmitter acetylcholine, and butyrylcholinesterase of unknown function. Several crystal structures of the former have shown that the active site is located at the bottom of a deep and narrow gorge, raising the question of how substrate and products enter and leave. Human butyrylcholinesterase (BChE) has attracted attention because it can hydrolyze toxic esters such as cocaine or scavenge organophosphorus pesticides and nerve agents. Here we report the crystal structures of several recombinant truncated human BChE complexes and conjugates and provide a description for mechanistically relevant non-productive substrate and product binding. As expected, the structure of BChE is similar to a previously published theoretical model of this enzyme and to the structure of Torpedo acetylcholinesterase. The main difference between the experimentally determined BChE structure and its model is found at the acyl binding pocket that is significantly bigger than expected. An electron density peak close to the catalytic Ser 198 has been modeled as bound butyrate.

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The key role of butyrylcholinesterase during neurogenesis and neural disorders: an antisense-5′butyrylcholinesterase-DNA study

Cited by 128 publications

References 69 publications

Design, Preparation, and Characterization of High-Activity Mutants of Human Butyrylcholinesterase Specific for Detoxification of Cocaine

Design, Preparation, and Characterization of High-Activity Mutants of Human Butyrylcholinesterase Specific for Detoxification of Cocaine

Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors

Crystal Structure of Human Butyrylcholinesterase and of Its Complexes with Substrate and Products

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