Design and Synthesis of Novel Dual Cholinesterase Inhibitors: <i>In Vitro</i> Inhibition Studies Supported with Molecular Docking

Koca, Mehmet; Güller, Uğur; Güller, Pınar; Dağalan, Ziya; Nişancı, Bilal

doi:10.1002/cbdv.202200015

Cited by 6 publications

(6 citation statements)

References 51 publications

(93 reference statements)

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“…Then Lineweaver–Burk graphs were drawn and K i constants were calculated (Figure 2). 32 While Tacrine (TAC) was used as standart inhibitor of cholinesterases, acetazolamide (AZA) was used as standard inhibitor of hCA isozymes 33,34 …”

Section: Methodsmentioning

confidence: 99%

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2‐Amino thiazole derivatives as inhibitors of some metabolic enzymes: An in vitro and in silico study

Korkmaz

2022

Biotech and App Biochem

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The thiazole derivatives are desirable compounds in the evaluation of their biological activities such as antiprotozoal antibacterial, antifungal, antituberculosis. Considering the medical application potential of 2‐amino thiazole compounds, we aimed to determine the effects of 2‐amino thiazole derivatives on the activities of carbonic anhydrase I–II isoenzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among the chemicals we used in our study, 2‐amino‐4‐(4‐chlorophenyl)thiazole compound exhibited the best inhibition against hCA I with Ki of 0.008 ± 0.001 μM. The 2‐amino‐4‐(4‐bromophenyl)thiazole compound exhibited the best inhibition against hCA II, AChE, and BChE with Ki of 0.124 ± 0.017, 0.129 ± 0.030, and 0.083 ± 0.041 μM, respectively. Molecular docking analysis showed that compound 2‐amino‐4‐(5,6,7,8‐tetrahydro‐2‐naphthyl)thiazole had the highest inhibitory potency against hCA I, hCA II, AChE, BChE with the estimated binding energy of −6.75, −7.61, −7.86, −7.96 kcal/mol, respectively.

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Section: Methodsmentioning

confidence: 99%

“…32 While Tacrine (TAC) was used as standart inhibitor of cholinesterases, acetazolamide (AZA) was used as standard inhibitor of hCA isozymes. 33,34…”

Section: In Vitro Inhibition Studiesmentioning

confidence: 99%

2‐Amino thiazole derivatives as inhibitors of some metabolic enzymes: An in vitro and in silico study

Korkmaz

2022

Biotech and App Biochem

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“…Therefore, increasing ACh stability towards catalyzed hydrolysis is the major approach to treating AD. [4][5][6][7][8][9][10] However, recent research has discovered a decreasing pH in the aging brain and Alzheimer's disease, [11] in which the enzyme becomes less active. [12] It implies that nonenzymatic hydrolysis potentially contributes to ACh depletion.…”

Section: Introductionmentioning

confidence: 99%

“…The enzyme is commonly believed to be the depletion's main origin. Therefore, increasing ACh stability towards catalyzed hydrolysis is the major approach to treating AD [4–10] . However, recent research has discovered a decreasing pH in the aging brain and Alzheimer's disease, [11] in which the enzyme becomes less active [12] .…”

Section: Introductionmentioning

confidence: 99%

Acetylcholine Conformational Flexibility and Its Neutral Hydrolysis in Aqueous Solution

et al. 2023

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Enzymatic hydrolysis is the main target to deal with ACh depletion. However, a recent study indicates that the nonenzymatic one may contribute to the depletion. This study highlights the necessity of considering possible conformers, discrete-continuum models, and dispersive effects for investigating the neutral (non-enzymatic) hydrolysis of flexible molecules in aqueous solution. We systematically built the possible conformers within the first-principles framework. The results confirm the reactivity of high-energy ACh conformer towards neutral hydrolysis. We proposed that conformational changes occur before the hydrolysis. The calculated activation and reaction energy shows that the discrete-continuum solvation model gives the closest result to experimental observations. This study also shows that neglecting dispersive effects brings unreliable structures in the initial state, which leads to unreliable activation energy.

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“…For example, Karunakaran et al (13) studied human AChE-inhibitory activity of Convolvulus pluricaulis (an herb) in zebrafish with scopolamine-induced cognitive dysfunction and result showed that the inhibitor was bound to His447 of the catalytic triad, anionic subsite, and peripheral anionic site. Koca et al (14) synthesized a benzamide derivative to investigate potency against cholinesterases with predicted inhibition profiles of the derivative. Furthermore, Makarian (11) analyzed the most potent derivatives of donepezil using molecular docking analysis and results showed different moieties of the new compound binding to all the subsites of the binding site.…”

Section: Introductionmentioning

confidence: 99%

In vitro inhibition of acetylcholinesterase activity by yellow field pea (Pisum sativum) protein-derived peptides as revealed by kinetics and molecular docking

et al. 2022

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Compounds with structural similarities to the neurotransmitter (acetylcholine) are mostly used to inhibit the activity of acetylcholinesterase (AChE) in Alzheimer’s disease (AD) therapy. However, the existing drugs only alleviate symptoms of moderate to mild conditions and come with side effects; hence, the search is still on for potent and safer options. In this study, High performance liquid chromatography (HPLC) fractionations of AChE-inhibitory pea protein hydrolysates obtained from alcalase, flavourzyme and pepsin digestions were carried out followed by sequence identification of the most active fractions using mass spectrometry. Subsequently, 20 novel peptide sequences identified from the active fractions were synthesized and five peptides, QSQS, LQHNA, SQSRS, ETRSQ, PQDER (IC50 = 1.53 – 1.61 μg/mL) were selected and analyzed for ability to change AChE protein conformation (fluorescence emission and circular dichroism), kinetics of enzyme inhibition, and enzyme-ligand binding configurations using molecular docking. The kinetics studies revealed different inhibition modes by the peptides with relatively low (<0.02 mM and <0.1 mM) inhibition constant and Michaelis constant, respectively, while maximum velocity was reduced. Conformational changes were confirmed by losses in fluorescence intensity and reduced α-helix content of AChE after interactions with different peptides. Molecular docking revealed binding of the peptides to both the catalytic anionic site and the peripheral anionic site. The five analyzed peptides all contained glutamine (Q) but sequences with Q in the penultimate N-terminal position (LQHNA, SQSRS, and PQDER) had stronger binding affinity. Results from the different analysis in this study confirm that the peptides obtained from enzymatic digestion of pea protein possess the potential to be used as novel AChE-inhibitory agents in AD management.

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Design and Synthesis of Novel Dual Cholinesterase Inhibitors: In Vitro Inhibition Studies Supported with Molecular Docking

Cited by 6 publications

References 51 publications

2‐Amino thiazole derivatives as inhibitors of some metabolic enzymes: An in vitro and in silico study

2‐Amino thiazole derivatives as inhibitors of some metabolic enzymes: An in vitro and in silico study

Acetylcholine Conformational Flexibility and Its Neutral Hydrolysis in Aqueous Solution

In vitro inhibition of acetylcholinesterase activity by yellow field pea (Pisum sativum) protein-derived peptides as revealed by kinetics and molecular docking

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