Dual BACE1 and Cholinesterase Inhibitory Effects of Phlorotannins from Ecklonia cava—An In Vitro and in Silico Study

Alzheimer′s disease (AD) is one of the most common neurodegenerative diseases with a multifactorial nature. β-Secretase (BACE1) and acetylcholinesterase (AChE), which are required for the production of neurotoxic β-amyloid (Aβ) and the promotion of Aβ fibril formation, respectively, are considered as prime therapeutic targets for AD. In our efforts towards the development of potent multi-target, directed agents for AD treatment, major phlorotannins such as eckol, dieckol, and 8,8′-bieckol from Ecklonia cava (E. cava) were evaluated. Based on the in vitro study, all tested compounds showed potent inhibitory effects on BACE1 and AChE. In particular, 8,8′-bieckol demonstrated the best inhibitory effect against BACE1 and AChE, with IC50 values of 1.62 ± 0.14 and 4.59 ± 0.32 µM, respectively. Overall, kinetic studies demonstrated that all the tested compounds acted as dual BACE1 and AChE inhibitors in a non-competitive or competitive fashion, respectively. In silico docking analysis exhibited that the lowest binding energies of all compounds were negative, and specifically different residues of each target enzyme interacted with hydroxyl groups of phlorotannins. The present study suggested that major phlorotannins derived from E. cava possess significant potential as drug candidates for therapeutic agents against AD.

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Synthesis, In vitro and In silico Evaluation of a Series of Pyrazolines as New Anticholinesterase Agents

Letters in Drug Design & Discovery ◽

10.2174/1570180816666190618111023 ◽

2020 ◽

Vol 17 (5) ◽

pp. 574-584

Author(s):

Mehlika Dilek Altıntop

Keyword(s):

Acetic Acid ◽

In Silico ◽

Structural Modification ◽

Inhibitory Effects ◽

In Silico Docking ◽

Ache Inhibitors ◽

Potential Applications ◽

Morpholine Derivatives ◽

Anticholinesterase Agents

Background: Pyrazolines, electron-rich nitrogen carriers, are of great importance due to their potential applications for the treatment of many diseases including inflammation, infectious diseases and neurodegenerative disorders. Objectives: The purpose of this work was to synthesize new pyrazoline derivatives and evaluate their anticholinesterase effects. Methods: 1-Aryl-5-[4-(piperidin-1-yl)phenyl]-3-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazoles (1-7) were synthesized via the treatment of 1-(3,4-dimethoxyphenyl)-3-[4-(piperidin-1-yl)phenyl]prop-2- en-1-one with arylhydrazine hydrochloride derivatives in acetic acid, whereas 1-aryl-5-[4- (morpholin-4-yl)phenyl]-3-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazoles (8-14) were obtained by the treatment of 1-(3,4-dimethoxyphenyl)-3-[4-(morpholin-4-yl)phenyl]prop-2-en-1-one with arylhydrazine hydrochloride derivatives in acetic acid. Their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were determined using a modification of Ellman’s spectrophotometric method. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were performed using Schrödinger’s Maestro molecular modeling package. Results: In general, piperidine derivatives were found to be more effective than morpholine derivatives on cholinesterases (ChEs). 1-Phenyl-5-[4-(piperidin-1-yl)phenyl]-3-(3,4-dimethoxyphenyl)- 4,5-dihydro-1H-pyrazole (1) and 1-(4-cyanophenyl)-5-[4-(piperidin-1-yl)phenyl]-3-(3,4- dimethoxyphenyl)-4,5-dihydro-1H-pyrazole (7) were identified as the most effective AChE inhibitors in this series with 40.92% and 38.98%, respectively. Compounds 1 and 7 were docked into the active site of human AChE (PDB code: 4EY7). Both the compounds were found to be capable of forming π-π stacking interactions with Trp286. Based on in silico ADME studies, these compounds are expected to have reasonable oral bioavailability. Conclusion: In the view of this work, the structural modification of the identified agents is going on for the generation of new anticholinesterase agents with enhanced efficacy.

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Computational and In-Vitro Validation of Natural Molecules as Potential Acetylcholinesterase Inhibitors and Neuroprotective Agents

Current Alzheimer Research ◽

10.2174/1567205016666181212155147 ◽

2019 ◽

Vol 16 (2) ◽

pp. 116-127 ◽

Cited By ~ 2

Author(s):

Ashwani Kumar ◽

Vineet Mehta ◽

Utkarsh Raj ◽

Pritish Kumar Varadwaj ◽

Malairaman Udayabanu ◽

...

Keyword(s):

In Silico ◽

Hippocampal Neurons ◽

Symptomatic Relief ◽

In Vitro Assays ◽

Disease Modifying Drugs ◽

In Silico Docking ◽

Ache Inhibitors ◽

Significant Difference ◽

Disease Modifying

Background: Cholinesterase inhibitors are the first line of therapy for the management of Alzheimer’s disease (AD), however, it is now established that they provide only temporary and symptomatic relief, besides, having several inherited side-effects. Therefore, an alternative drug discovery method is used to identify new and safer ‘disease-modifying drugs’. Methods: Herein, we screened 646 small molecules of natural origin having reported pharmacological and functional values through in-silico docking studies to predict safer neuromodulatory molecules with potential to modulate acetylcholine metabolism. Further, the potential of the predicted molecules to inhibit acetylcholinesterase (AChE) activity and their ability to protect neurons from degeneration was determined through in-vitro assays. Results: Based on in-silico AChE interaction studies, we predicted quercetin, caffeine, ascorbic acid and gallic acid to be potential AChE inhibitors. We confirmed the AChE inhibitory potential of these molecules through in-vitro AChE inhibition assay and compared results with donepezil and begacestat. Herbal molecules significantly inhibited enzyme activity and inhibition for quercetin and caffeine did not show any significant difference from donepezil. Further, the tested molecules did not show any neurotoxicity against primary (E18) hippocampal neurons. We observed that quercetin and caffeine significantly improved neuronal survival and efficiently protected hippocampal neurons from HgCl2 induced neurodegeneration, which other molecules, including donepezil and begacestat, failed to do. Conclusion: Quercetin and caffeine have the potential as “disease-modifying drugs” and may find application in the management of neurological disorders such as AD.

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in Silico Docking and Molecular Dynamic Simulation of 3-Dehydroquinate Dehydratase from Mycobacterium Tuberculosis Through Virtual Screening and Pharmacokinetics Studies

10.26434/chemrxiv.12498155.v1 ◽

2020 ◽

Author(s):

Mustafa Alhaji Isa ◽

Muhammad M Ibrahim

Keyword(s):

Mycobacterium Tuberculosis ◽

Virtual Screening ◽

Molecular Dynamic ◽

In Silico ◽

Md Simulation ◽

Binding Energies ◽

In Silico Docking ◽

Pharmacokinetic Properties

The 3-hydroquinate synthase (DHQase) is an enzyme that catalyzes the third step of the shikimate pathway in <i>Mycobacterium tuberculosis</i> (MTB), by converting 3-dehydroquinate into 3-dehydroshikimate. In this study, the novel inhibitors of DHQase from MTB was identified using in silico approach. The crystal structure of DHQase bound to 1,3,4-trihydroxy-5-(3-phenoxypropyl)-cyclohexane-1-carboxylic acid (CA) obtained from the Protein Data Bank (PDB ID: 3N76). The structure prepared through energy minimization and structure optimization. A total of 9699 compounds obtained from Zinc and PubChem databases capable of binding to DHQase and subjected to virtual screening through Lipinski’s rule of five and molecular docking analysis. Eight (8) compounds with good binding energies, ranged between ─8.99 to ─8.39kcal/mol were selected, better than the binding energy of ─4.93kcal/mol for CA and further filtered for pharmacokinetic properties (Absorption, Distribution, Metabolism, Excretion, and Toxicity or ADMET). Five compounds (ZINC14981770, ZINC14741224, ZINC14743698, ZINC13165465, and ZINC8442077) which had desirable pharmacokinetic properties selected for molecular dynamic (MD) simulation and molecular generalized born surface area (MM-GBSA) analyses. The results of the analyses showed that all the compounds formed stable and rigid complexes after the 50ns MD simulation and also had a lower binding as compared to CA. Therefore, these compounds considered as good inhibitors of MTB after in vitro and in vivo validation.”

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In silico Structure-based Identification of Novel Acetylcholinesterase Inhibitors Against Alzheimer’s Disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527317666180115162422 ◽

2018 ◽

Vol 17 (1) ◽

pp. 54-68 ◽

Cited By ~ 12

Author(s):

Kanzal Iman ◽

Muhammad Usman Mirza ◽

Nauman Mazhar ◽

Michiel Vanmeert ◽

Imran Irshad ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

In Silico ◽

Neurodegenerative Disorder ◽

In Silico Analysis ◽

Acetylcholinesterase Inhibitors ◽

Binding Energies ◽

Therapeutic Interventions ◽

Ache Inhibitors

Objective and Background: Inhibition of acetylcholinesterase (AChE) has gained much importance since the discovery of the involvement of peripheral anionic site as an allosteric regulator of AChE. Characterized by the formation of β-amyloid plaques, Alzheimer's disease (AD) is currently one of the leading causes of death across the world. Progression in this neurodegenerative disorder causes deficit in the cholinergic activity that leads towards cognitive decline. Therapeutic interventions in AD are largely focused upon AChE inhibitors designed essentially to prevent the loss of cholinergic function. The multifactorial AD pathology calls for Multitarget-directed ligands (MTDLs) to follow up on various components of the disease. Considering this approach, other related AD targets were also selected. Structure-based virtual screening was relied upon for the identification of lead compounds with anti-AD effect. Method: Several chemoinformatics approaches were used in this study, reporting four multi-target inhibitors: MCULE-7149246649-0-1, MCULE-6730554226-0-4, MCULE-1176268617-0-6 and MCULE-8592892575-0-1 with high binding energies that indicate better AChE inhibitory activity. Additional in-silico analysis hypothesized the abundant presence of aromatic interactions to be pivotal for interaction of selected compounds to the acetyl-cholinesterase. Additionally, we presented an alternative approach to determine protein-ligand stability by calculating the Gibbs-free energy change over time. Furthermore, this allows to rank potential hits for further in-vitro testing. Results and Conclusion: With no predicted indication of adverse effects on humans, this study unravels four active multi-target inhibitors against AChE with promising affinities and good ADMET profile for the potential use in AD treatment.

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α-Glucosidase inhibitors: consistency of in silico docking data with in vitro inhibitory data and inhibitory effect prediction of quercetin derivatives

Food & Function ◽

10.1039/c9fo01333d ◽

2019 ◽

Vol 10 (10) ◽

pp. 6312-6321 ◽

Cited By ~ 5

Author(s):

Jianzhong Zhu ◽

Bin Zhang ◽

Chinping Tan ◽

Qiang Huang

Keyword(s):

In Silico ◽

Inhibitory Effect ◽

Inhibitory Effects ◽

Quercetin Derivatives ◽

In Silico Docking ◽

Glucosidase Inhibitors ◽

The Relationship

The relationship between in silico and in vitro experiments regarding the inhibitory effects of polyphenols on α-glucosidase was investigated.

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In vitro antibacterial and in silico docking studies of two Schiff bases on Staphylococcus aureus and its target proteins

Future Journal of Pharmaceutical Sciences ◽

10.1186/s43094-021-00225-3 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Ragi K ◽

Joby Thomas Kakkassery ◽

Vinod P. Raphael ◽

Reeja Johnson ◽

Vidhya Thomas K

Keyword(s):

Staphylococcus Aureus ◽

Schiff Base ◽

Schiff Bases ◽

Dihydrofolate Reductase ◽

In Silico ◽

Docking Studies ◽

Binding Energies ◽

Target Proteins ◽

In Silico Docking

Abstract Background Schiff base compounds have extensive applications in various fields such as analytical, inorganic, organic, and biological fields. They have excellent pharmacology application prospects in the modern era and are widely used in the pharmaceutical industry. In the present work in vitro antibacterial and in silico docking studies of two Schiff base compounds 2,2’-(5,5-dimethylcyclohexane-1,3-diylidene)bis(azan-1-yl-1-ylidene)diphenol (DmChDp) and N,N’-(5,5-dimethylcyclohexane-1,3-diylidene)dianiline (DmChDa) were carried out against the bacterial strain Staphylococcus aureus and its target proteins. Results The tests proved that the ligands have potential antibacterial activity. In the computational analysis, the drug-like properties of the compounds were first pre-filtered using the Lipinski rule of five. Then, molecular docking study was conducted using the AutoDock 4.2 program, to establish the mechanism by which the molecules inhibit the growth of S. aureus. For this purpose, 6 different target proteins (PDB ID: 1T2P, 3U2D, 2W9S, 1N67, 2ZCO, and 4H8E) of S. aureus were selected. Both the Schiff bases showed a good binding affinity with the target protein dihydrofolate reductase enzyme (PDB ID: 2W9S) but in different sites. Maximum binding energies of about − 10.3 and − 10.2 kcal/mol were observed when DmChDp and DmChDa were docked with 2W9S. Conclusion Schiff base compounds DmChDp and DmChDa have appreciable growth-inhibitory power against S. aureus, which can be attributed to the deactivation of the enzyme, dihydrofolate reductase.

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In vitro anti-inflammatory resorcinol derivatives and their in silico analysis

Can Tho University Journal of Science ◽

10.22144/ctu.jen.2020.027 ◽

2020 ◽

Vol 12 (3) ◽

Author(s):

Rahen Mahmuda ◽

Tran Quang De ◽

Negar Sultana Shoshi ◽

Khadija Akhter Poly ◽

Pranoy Saha ◽

...

Keyword(s):

In Silico ◽

In Silico Analysis ◽

Hydroxyl Groups ◽

Binding Modes ◽

Docking Analysis ◽

In Silico Docking ◽

Lead Generation ◽

Anti Inflammatory ◽

Dose Dependent

Resorcinol with its two hydroxyl groups was derivatized in laboratory to observe the anti-inflammatory potential in vitro. Subsequently in silico docking analysis was done for observing the binding modes in cyclooxygenase enzyme to have idea about the subsequent possible developments. At the doses of 200 mg/ml and 400 mg/ml. the compounds showed the anti-inflammatory property, where 02 offered dose dependent 51% and 70% of inhibition of heat induced hemolysis respectively. The scaffold thus poses as an interesting pharmacophore suitable for lead generation for the inflammatory disorders.

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in Silico Docking and Molecular Dynamic Simulation of 3-Dehydroquinate Dehydratase from Mycobacterium Tuberculosis Through Virtual Screening and Pharmacokinetics Studies

10.26434/chemrxiv.12498155 ◽

2020 ◽

Author(s):

Mustafa Alhaji Isa ◽

Muhammad M Ibrahim

Keyword(s):

Mycobacterium Tuberculosis ◽

Virtual Screening ◽

Molecular Dynamic ◽

In Silico ◽

Md Simulation ◽

Binding Energies ◽

In Silico Docking ◽

Pharmacokinetic Properties

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2,4-Dioxochroman Moiety Linked to 1,2,3-triazole Derivatives as Novel α-glucosidase Inhibitors: Synthesis, In vitro Biological Evaluation, and Docking Study

Current Organic Chemistry ◽

10.2174/1385272824999200802181634 ◽

2020 ◽

Vol 24 (17) ◽

pp. 2019-2027 ◽

Cited By ~ 1

Author(s):

Marjan Mollazadeh ◽

Maryam Mohammadi-Khanaposhtani ◽

Yousef Valizadeh ◽

Afsaneh Zonouzi ◽

Mohammad Ali Faramarzi ◽

...

Keyword(s):

In Silico ◽

Click Reaction ◽

Docking Study ◽

Competitive Inhibitor ◽

Biological Evaluation ◽

Binding Energies ◽

Standard Drug ◽

In Silico Docking ◽

Glucosidase Inhibitors

In this study, a novel series of 2,4-dioxochroman-1,2,3-triazole hybrids 8a-l was synthesized by click reaction. These compounds were screened against α-glucosidase through in vitro and in silico evaluations. All the synthesized hybrids exhibited excellent α-glucosidase inhibition in comparison to standard drug acarbose. Representatively, 3-((((1-(3,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)amino)methylene)chroman-2,4- dione 8h with IC50 = 20.1 ± 1.5 μM against α-glucosidase, was 37-times more potent than acarbose. Enzyme kinetic study revealed that compound 8h was a competitive inhibitor against α-glucosidase. In silico docking study on chloro derivatives 8h, 8g, and 8i were also performed in the active site of α -glucosidase. Evaluations on obtained interaction modes and binding energies of these compounds confirmed the results obtained through in vitro α-glucosidase inhibition.

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ANTICANCER ACTIVITY OF Β-SITOSTEROL FROM PLECTRANTHUS AMBOINICUS (LOUR. SPRENG.) LEAVES: IN VITRO AND IN SILICO STUDIES

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2017.v10i5.16931 ◽

2017 ◽

Vol 10 (5) ◽

pp. 306

Author(s):

Denny Satria ◽

Poppy Anjelisa Zaitun Hasibuan ◽

Panal Sitorus

Keyword(s):

In Silico ◽

Estrogen Receptor Alpha ◽

In Vitro Study ◽

Three Dimensions ◽

Three Dimension ◽

Docking Score ◽

In Silico Docking ◽

In Silico Studies ◽

Her 2

Objective: β-sitosterol is the steroid compound which is an important nutrient in the diet meal, hydrophobic and soluble in organic solvents and considered as a good biomarker due to its biological activity.Methods: In vitro study was using 2,5-diphenyl tetrazolium bromide method towards T47D, MCF-7, HeLa, and WiDr cell lines. In silico docking using PLANTS program and visualized by Yasara program. The model of three dimension enzyme structures used in this research were epidermal growth factor receptor (EGFR), phosphatidylinositol-3-kinase (PI3K), estrogen receptor-alpha (ER-α), ER-beta (ER-β), and human EGFR 2 (HER-2). Two and three dimensions of β-sitosetrol, ZSTK474, and tamoxifen as the standard were generated using Marvin Sketch program.Results: β-sitosterol was found to have inhibitory concentration 50% of 0.55; 0.87; 0.76, and 0.99 mM. β-sitosterol and ZSTK474 were inhibited EGFR and PI3K with docking score −92.8195; −91.7920 and −91.7470; −94.7491 β-sitosterol and tamoxifen were inhibited ER-α, ER-β and HER-2 with docking score −78.5570; −89.535, −68.7717; −52.008 and −90.4908; −50.5576, respectively.Conclusion: Based on the results above that shows β-sitosterol provide effective as anticancer.Keywords: β-sitosterol, Inhibitor, Anticancer, In vitro, In silico.

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