Three-dimensional quantitative structure–activity relationship (3D-QSAR) analyses of choline acetyltransferase inhibitors

Chandrasekaran, V.; McGaughey, Georgia B.; Cavallito, Chester J.; Bowen, J. Phillip

doi:10.1016/j.jmgm.2004.04.002

Cited by 9 publications

(3 citation statements)

References 21 publications

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“…The best model developed contained the combination of A/B/C/Ch components, which gave highest cross validated correlation coefficient (a Q 2 value of 0.809). Our Hologram QSAR results are in close agreement with an earlier study based on CoMFA and CoMSIA modeling 25 . For instance in agreement with our findings, their results indicated that a pyridine ring, which is one of the most common functional group among the parent compounds, had major contribution towards the affinity for ChAT.…”

Section: Discussionsupporting

confidence: 91%

Novel ligands of Choline Acetyltransferase designed by in silico molecular docking, hologram QSAR and lead optimization

Kumar

Långström

Darreh‐Shori

2016

Sci Rep

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Recent reports have brought back the acetylcholine synthesizing enzyme, choline acetyltransferase in the mainstream research in dementia and the cholinergic anti-inflammatory pathway. Here we report, a specific strategy for the design of novel ChAT ligands based on molecular docking, Hologram Quantitative Structure Activity Relationship (HQSAR) and lead optimization. Molecular docking was performed on a series of ChAT inhibitors to decipher the molecular fingerprint of their interaction with the active site of ChAT. Then robust statistical fragment HQSAR models were developed. A library of novel ligands was generated based on the pharmacophoric and shape similarity scoring function, and evaluated in silico for their molecular interactions with ChAT. Ten of the top scoring invented compounds are reported here. We confirmed the activity of α-NETA, the only commercially available ChAT inhibitor, and one of the seed compounds in our model, using a new simple colorimetric ChAT assay (IC50 ~ 88 nM). In contrast, α-NETA exhibited an IC50 of ~30 μM for the ACh-degrading cholinesterases. In conclusion, the overall results may provide useful insight for discovering novel ChAT ligands and potential positron emission tomography tracers as in vivo functional biomarkers of the health of central cholinergic system in neurodegenerative disorders, such as Alzheimer’s disease.

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Section: Discussionsupporting

confidence: 91%

Novel ligands of Choline Acetyltransferase designed by in silico molecular docking, hologram QSAR and lead optimization

Kumar

Långström

Darreh‐Shori

2016

Sci Rep

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“…[9] While AV Ps are reasonably potent in vitro,their confounding pharmacological profile, [10,11] their propensity to photoisomerize, [12] their electrophilic scaffold, and their permanent charge limits their usefulness in many applications.F urthermore,the mechanism of ChATinhibition by AV Ps is hitherto unknown, [13][14][15] and the structure-activity relationships (SAR) of these compounds have yielded few clues as to how they could be improved. [16] In addition to AV Ps,a ryl-3-oxopropanaminium compounds (e.g alfa-NETA) are known inhibitors of ChAT, [17] and ar ecent work by Darreh-Shori and coworkers have identified commercially available compounds by virtual screening that show inhibitory activity in in vitro assays. [18,19] ChATc atalyses the synthesis of AChfrom choline,u sing acetylcoenzyme A( AcCoA,F igure 1) as the acyl donor.…”

Section: Introductionmentioning

confidence: 99%

In Situ Assembly of Choline Acetyltransferase Ligands by a Hydrothiolation Reaction Reveals Key Determinants for Inhibitor Design

et al. 2020

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The potential drug target choline acetyltransferase (ChAT) catalyses the production of the neurotransmitter acetylcholine in cholinergic neurons, T‐cells, and B‐cells. Herein, we show that arylvinylpyridiniums (AVPs), the most widely studied class of ChAT inhibitors, act as substrate in an unusual coenzyme A‐dependent hydrothiolation reaction. This in situ synthesis yields an adduct that is the actual enzyme inhibitor. The adduct is deeply buried in the active site tunnel of ChAT and interactions with a hydrophobic pocket near the choline binding site have major implications for the molecular recognition of inhibitors. Our findings clarify the inhibition mechanism of AVPs, establish a drug modality that exploits a target‐catalysed reaction between exogenous and endogenous precursors, and provide new directions for the development of ChAT inhibitors with improved potency and bioactivity.

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“…There is a large number of quantitative structure-activity relationship (QSAR) studies concerning the chemical structure and corresponding biological information for AChE inhibitors [9][10][11][12][13]. However, the lack of comparable studies associated with BuChE prompted us to develop QSAR models for this class of attractive enzyme inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Classical and Hologram QSAR Studies on a Series of Tacrine Derivatives as Butyrylcholinesterase Inhibitors

Castilho¹,

Güido

Andricopulo

2007

LDDD

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Alzheimer's disease (AD) is a major neurodegenerative disease that affects mainly people over 65 years of age. The main therapeutic approach to AD is based on the use of acetylcholinesterase (AChE) inhibitors. Recent studies have shown that butyrylcholinesterase (BuChE) can also be considered an attractive target for the development of novel drugs for AD therapy. The design of new potent and selective BuChE inhibitors is of great importance in drug discovery. 2D quantitative structure-activity relationship studies were conducted on a series of potent inhibitors of human BuChE using classical and hologram QSAR (HQSAR) approaches. A training set of 40 compounds was employed to derive the models. Classical QSAR models showed moderate correlation (r 2 = 0.836, q 2 = 0.750), with no substantial predictive power for untested compounds. On the other hand, the best HQSAR model (r 2 = 0.928, q 2 = 0.723) was used to predict the potency of 10 test set compounds, and the predicted values were in good agreement with the experimental results, showing the potential of this model for new untested compounds.

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Three-dimensional quantitative structure–activity relationship (3D-QSAR) analyses of choline acetyltransferase inhibitors

Cited by 9 publications

References 21 publications

Novel ligands of Choline Acetyltransferase designed by in silico molecular docking, hologram QSAR and lead optimization

Novel ligands of Choline Acetyltransferase designed by in silico molecular docking, hologram QSAR and lead optimization

In Situ Assembly of Choline Acetyltransferase Ligands by a Hydrothiolation Reaction Reveals Key Determinants for Inhibitor Design

Classical and Hologram QSAR Studies on a Series of Tacrine Derivatives as Butyrylcholinesterase Inhibitors

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