Microscopic binding of butyrylcholinesterase with quinazolinimine derivatives and the structure–activity correlation

Theoretical Chemistry Accounts (Impact Factor: 2.23). 09/2011; 130(1):69-82. DOI: 10.1007/s00214-011-0965-1


Butyrylcholinesterase (BChE) is not only an important protein for development of anti-cocaine medication but also an established
drug target to develop new treatment for Alzheimer’s disease (AD). The molecular basis of interaction of a new series of quinazolinimine
derivatives as BChE inhibitors has been studied by molecular docking and molecular dynamics (MD) simulations. The molecular
docking and MD simulations revealed that all of these inhibitors bind with BChE in similar binding mode. Based on the similar
binding mode, we have carried out three-dimensional quantitative structure–activity relationship (3D-QSAR) studies on these
inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA),
to understand the structure–activity correlation of this series of inhibitors and to develop predictive models that could
be used in the design of new inhibitors of BChE. The study has resulted in satisfactory 3D-QSAR models. We have also developed
ligand-based 3D-QSAR models. The contour maps obtained from the 3D-QSAR models in combination with the simulated binding structures
help to better interpret the structure–activity relationship and is consistent with available experimental activity data.
The satisfactory 3D-QSAR models strongly suggest that the determined BChE-inhibitor binding modes are reasonable. The identified
binding modes and developed 3D-QSAR models for these BChE inhibitors are expected to be valuable for rational design of new
BChE inhibitors that may be valuable in the treatment of Alzheimer’s disease.

KeywordsButyrylcholinesterase–Inhibitor–Binding mode–Modeling

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    ABSTRACT: 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: r(2)=0.67, rmsd=0.87, q(2)=0.65 and loormsd=0.90; the statistical results for the ligand-based MLR model were: r(2)=0.89, rmsd=0.51, q(2)=0.85 and loormsd=0.58; the statistical results for the ligand-based NN model were the best: r(2)=0.95, rmsd=0.33, q(2)=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 developed 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.
    No preview · Article · Nov 2013 · Bioorganic & medicinal chemistry
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    ABSTRACT: A striking dual inhibition of enzymes α-glucosidase and butyrylcholinesterase by small drug-like molecules, including 1,4-disubstituted-1,2,3-triazoles, chalcones, and benzothiazepines, was rationalized with the help of Molecular Field Topology Analysis, a 3D QSAR technique similar to CoMFA. A common pharmacophore supported the concept of a link existing between type-2 diabetes mellitus and Alzheimer's disease. These findings will be instrumental for rational design of drug candidates for both of these conditions.
    Full-text · Article · Apr 2014 · European Journal of Medicinal Chemistry
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    ABSTRACT: Selective and nanomolar acetylcholinesterase inhibitors were obtained by connecting tri- and tetracyclic quinazolinones-previously described as moderately active and unselective cholinesterase (ChE) inhibitors-via a hydroxyl group in para position to an anilinic nitrogen with different amines linked via a three carbon atom spacer. These tri- and tetracyclic quinazolinones containing different alicyclic ring sizes and connected to tertiary amines were docked to a high-resolution hAChE crystal structure to investigate the preferred binding mode in relation to results obtained by experimental structure-activity relationships. While the 'classical orientation' locating the heterocycle in the active site was rarely found, an alternative binding mode with the basic aliphatic amine in the active center ('inverted' orientation) was obtained for most compounds. Analyses of extended SARs based on this inverted binding mode are able to explain the compounds' binding affinities at AChE.
    Full-text · Article · Jul 2014 · Bioorganic & Medicinal Chemistry