Acetylcholinesterase and butyrylcholinesterase inhibitory activities of khellactone coumarin derivatives isolated from Peucedanum japonicum Thurnberg

AbstractCholinesterase (ChE) and monoamine oxidase (MAO) inhibitors have been attracted as candidate treatments for Alzheimer's disease (AD). Fifteen khellactone-type coumarins from the roots of Peucedanum japonicum Thunberg were tested for acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and MAO inhibitory activities. Compound 3′-angeloyl-4′-(2-methylbutyryl)khellactone (PJ13) most potently inhibited AChE (IC50 = 9.28 µM), followed by 3′-isovaleryl-4′-(2-methylbutyroyl)khellactone (PJ15) (IC50 = 10.0 μM). Compound senecioyl-4′-angeloyl-khellactone (PJ5) most potently inhibited BChE (IC50 = 7.22 μM) and had the highest selectivity index (> 5.54), followed by 3′-senecioyl-4′-(2-methylbutyryl)khellactone (PJ10) and 3′,4′-disenecioylkhellactone (PJ4) (IC50 = 10.2 and 10.7 μM, respectively). Compounds PJ13, PJ15, and PJ5 showed reversible and mixed-types of inhibition with Ki values of 5.98, 10.4 (for AChE), and 4.16 µM (for BChE), respectively. However, all 15 compounds weakly inhibited MAO-A and MAO-B. Molecular docking simulation revealed that PJ13 had a higher binding affinity (− 9.3 kcal/mol) with AChE than PJ15 (− 7.8 kcal/mol) or PJ5 (− 5.4 kcal/mol), due to the formation of a hydrogen bond with Tyr121 (distance: 2.52 Å). On the other hand, the binding affinity of PJ5 (− 10.0 kcal/mol) with BChE was higher than for PJ13 (− 7.7 kcal/mol) or PJ15 (− 8.1 kcal/mol), due to the formation of a hydrogen bond with Ser198 (distance: 2.05 Å). These results suggest that PJ13 and PJ5 are potential reversible selective inhibitors of AChE and BChE, respectively, for the treatment of AD.

Download Full-text

Development of Halogenated Pyrazolines as Selective Monoamine Oxidase-B Inhibitors: Deciphering via Molecular Dynamics Approach

Molecules ◽

10.3390/molecules26113264 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3264

Author(s):

Aathira Sujathan Nair ◽

Jong-Min Oh ◽

Vishal Payyalot Koyiparambath ◽

Sunil Kumar ◽

Sachithra Thazhathuveedu Sudevan ◽

...

Keyword(s):

Molecular Dynamics ◽

Monoamine Oxidase ◽

Phenyl Ring ◽

Competitive Inhibitor ◽

Selectivity Index ◽

Monoamine Oxidase A ◽

Mao B ◽

Ic50 Value ◽

The Central Nervous System ◽

Inhibitory Activities

Halogens have been reported to play a major role in the inhibition of monoamine oxidase (MAO), relating to diverse cognitive functions of the central nervous system. Pyrazoline/halogenated pyrazolines were investigated for their inhibitory activities against human monoamine oxidase-A and -B. Halogen substitutions on the phenyl ring located at the fifth position of pyrazoline showed potent MAO-B inhibition. Compound 3-(4-ethoxyphenyl)-5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole (EH7) showed the highest potency against MAO-B with an IC50 value of 0.063 µM. The potencies against MAO-B were increased in the order of –F (in EH7) > –Cl (EH6) > –Br (EH8) > –H (EH1). The residual activities of most compounds for MAO-A were > 50% at 10 µM, except for EH7 and EH8 (IC50 = 8.38 and 4.31 µM, respectively). EH7 showed the highest selectivity index (SI) value of 133.0 for MAO-B, followed by EH6 at > 55.8. EH7 was a reversible and competitive inhibitor of MAO-B in kinetic and reversibility experiments with a Ki value of 0.034 ± 0.0067 µM. The molecular dynamics study documented that EH7 had a good binding affinity and motional movement within the active site with high stability. It was observed by MM-PBSA that the chirality had little effect on the overall binding of EH7 to MAO-B. Thus, EH7 can be employed for the development of lead molecules for the treatment of various neurodegenerative disorders.

Download Full-text

Inhibition of Butyrylcholinesterase by Glycyrol, a Coumarin, Isolated from Glycyrrhiza Uralensis

10.20944/preprints202008.0306.v1 ◽

2020 ◽

Author(s):

Geum Seok Jeong ◽

Myung-Gyun Kang ◽

Joon Yeop Lee ◽

Sang Ryong Lee ◽

Daeui Park ◽

...

Keyword(s):

Binding Affinity ◽

Competitive Inhibitor ◽

Glycyrrhiza Uralensis ◽

Form Hydrogen Bond ◽

Docking Simulations ◽

Mao B ◽

Mao A ◽

Ic50 Values ◽

Noncompetitive Inhibitor ◽

Inhibitory Activities

Eight compounds were isolated from the roots of Glycyrrhiza uralensis and tested for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activities. Glycyrol (GC) effectively inhibited butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) with IC50 values of 7.22 and 14.77 µM, respectively, and also moderately inhibited MAO-B (29.48 µM). Six of the other seven compounds only weakly inhibited AChE and BChE, whereas liquiritin apioside moderately inhibited AChE (IC50 = 36.68 µM). Liquiritigenin (LG) potently inhibited MAO-B (IC50 = 0.098 µM) and MAO-A (IC50 = 0.27 µM), and liquiritin, a glycoside of LG, weakly inhibited MAO-B (&gt; 40 µM). GC was a reversible, noncompetitive inhibitor of BChE with a Ki value of 4.47 µM, and LG was a reversible competitive inhibitor of MAO-B with a Ki value of 0.024 µM. Docking simulations showed that the binding affinity of GC for BChE (-7.8 kcal/mol) was greater than its affinity for AChE (-7.1 kcal/mol), and suggested that GC interacted with BChE at Thr284 and Val288 by hydrogen bonds (distances: 2.42 and 1.92 Å, respectively) beyond the ligand binding site of BChE, but that GC did not form hydrogen bond with AChE. The binding affinity of LG for MAO-B (-8.8 kcal/mol) was greater than its affinity for MAO-A (-7.9 kcal/mol). These findings suggest GC and LG should be considered promising compounds for the treatment of Alzheimer’s disease with multi-targeting activities.

Download Full-text

Docking Characterization and in vitro Inhibitory Activity of Flavan-3-ols and Dimeric Proanthocyanidins Against the Main Protease Activity of SARS-Cov-2

Frontiers in Plant Science ◽

10.3389/fpls.2020.601316 ◽

2020 ◽

Vol 11 ◽

Cited By ~ 2

Author(s):

Yue Zhu ◽

De-Yu Xie

Keyword(s):

Hydrogen Bonds ◽

Inhibitory Activity ◽

Docking Simulation ◽

Binding Pocket ◽

Structural Features ◽

The Other ◽

Main Protease ◽

Inhibitory Activities ◽

The One

We report to use the main protease (Mpro) of SARS-Cov-2 to screen plant flavan-3-ols and proanthocyanidins. Twelve compounds, (–)-afzelechin (AF), (–)-epiafzelechin (EAF), (+)-catechin (CA), (–)-epicatechin (EC), (+)-gallocatechin (GC), (–)-epigallocatechin (EGC), (+)-catechin-3-O-gallate (CAG), (–)-epicatechin-3-O-gallate (ECG), (–)-gallocatechin-3-O-gallate (GCG), (–)-epigallocatechin-3-O-gallate (EGCG), procyanidin A2 (PA2), and procyanidin B2 (PB2), were selected for docking simulation. The resulting data predicted that all 12 metabolites could bind to Mpro. The affinity scores of PA2 and PB2 were predicted to be −9.2, followed by ECG, GCG, EGCG, and CAG, −8.3 to −8.7, and then six flavan-3-ol aglycones, −7.0 to −7.7. Docking characterization predicted that these compounds bound to three or four subsites (S1, S1′, S2, and S4) in the binding pocket of Mpro via different spatial ways and various formation of one to four hydrogen bonds. In vitro analysis with 10 available compounds showed that CAG, ECG, GCG, EGCG, and PB2 inhibited the Mpro activity with an IC50 value, 2.98 ± 0.21, 5.21 ± 0.5, 6.38 ± 0.5, 7.51 ± 0.21, and 75.3 ± 1.29 μM, respectively, while CA, EC, EGC, GC, and PA2 did not have inhibitory activities. To further substantiate the inhibitory activities, extracts prepared from green tea (GT), two muscadine grapes (MG), cacao, and dark chocolate (DC), which are rich in CAG, ECG, GAG, EGCG, or/and PB2, were used for inhibitory assay. The resulting data showed that GT, two MG, cacao, and DC extracts inhibited the Mpro activity with an IC50 value, 2.84 ± 0.25, 29.54 ± 0.41, 29.93 ± 0.83, 153.3 ± 47.3, and 256.39 ± 66.3 μg/ml, respectively. These findings indicate that on the one hand, the structural features of flavan-3-ols are closely associated with the affinity scores; on the other hand, the galloylation and oligomeric types of flavan-3-ols are critical in creating the inhibitory activity against the Mpro activity.

Download Full-text

in silico Anti-Cholinestarase Activity of Flavonoids: A Computational Approach

Asian Journal of Chemistry ◽

10.14233/ajchem.2019.22153 ◽

2019 ◽

Vol 31 (12) ◽

pp. 2859-2864

Author(s):

Niraj Kumar Singh ◽

Somdutt Mujwar ◽

Debapriya Garabadu

Keyword(s):

Molecular Docking ◽

Binding Affinity ◽

Docking Simulation ◽

Docking Studies ◽

Computational Approach ◽

Molecular Docking Simulation ◽

Flavonoid Compounds ◽

Potent Inhibition ◽

Potential Binding ◽

Derivatives Of

In the present study, a computational approach has been designed to evaluate the potential anti-cholinesterase activity of derivatives of flavonoids. Molecular docking studies is performed for the 9 flavonoids against the human acetylcholine (ACh) enzyme to evaluate their binding affinity for having anti-alzheimer activity. All the 9 flavonoid compounds exhibited strong binding affinity that promises potent inhibition of human acetylcholine enzyme. Potential binding affinity of all the flavonoids against human acetylcholine enzyme confirms their possible mechanism of action by using AutoDock based molecular docking simulation technique. Thus, these flavonoid compounds could be presumed to be potential anti-cholinesterase drugs.

Download Full-text

Synthesis of 1,3,4-oxadiazoles as promising anticoagulant agents

RSC Advances ◽

10.1039/c6ra01158f ◽

2016 ◽

Vol 6 (29) ◽

pp. 24797-24807 ◽

Cited By ~ 4

Author(s):

Vishwanathan B. Iyer ◽

Gurupadayya B. M. ◽

Bharathkumar Inturi ◽

Venkata Sairam K. ◽

Gurubasavaraj V. Pujar

Keyword(s):

Molecular Docking ◽

Binding Affinity ◽

Vitamin K ◽

Factor Xa ◽

Docking Simulation ◽

Molecular Docking Simulation ◽

Vitamin K Epoxide Reductase ◽

Target Proteins ◽

Anticoagulant Agents ◽

Epoxide Reductase

A series of 1,3,4-oxadiazoles were designed and subjected to molecular docking simulation onto the enzymes vitamin K epoxide reductase (PDB: 3KP9) and factor Xa (PDB: 1NFY) to visualize their binding affinity towards the said target proteins.

Download Full-text

Homology modeling and molecular docking simulation of some novel imidazo[1,2-a]pyridine-3-carboxamide (IPA) series as inhibitors of Mycobacterium tuberculosis

Journal of Genetic Engineering and Biotechnology ◽

10.1186/s43141-020-00102-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Mustapha Abdullahi ◽

Shola Elijah Adeniji ◽

David Ebuka Arthur ◽

Abdurrashid Haruna

Keyword(s):

Mycobacterium Tuberculosis ◽

Molecular Docking ◽

Homology Modeling ◽

Binding Affinity ◽

Docking Simulation ◽

Computational Method ◽

Multiple Drug ◽

Drug Resistant ◽

Standard Drug ◽

Molecular Docking Simulation

Abstract Background Tuberculosis (TB) remains a serious global health challenge that is caused by Mycobacterium tuberculosis and has killed numerous people. This necessitated the urgent need for the hunt and development of more potent drugs against the fast-emerging extensively drug-resistant (XDR) and multiple-drug-resistant (MDR) M. tuberculosis strains. Mycobacterium tuberculosis cytochrome b subunit of the cytochrome bc1 complex (QcrB) was recognized as a potential drug target in M. tuberculosis (25618/H37Rv) for imidazo[1,2-a]pyridine-3-carboxamides whose crystal strucuture is not yet reported in the Protein Data Bank (PDB). The concept of homology modeling as a powerful and useful computational method can be applied, since the M. tuberculosis QcrB protein sequence data are available. Results The homology model of QcrB protein in M. tuberculosis was built from the X-ray structure of QcrB in M. smegmatis as a template using the Swiss-Model online workspace. The modeled protein was assessed, validated, and prepared for the molecular docking simulation of 35 ligands of N-(2-phenoxy)ethyl imidazo[1,2-a] pyridine-3-carboxamide (IPA) to analyze their theoretical binding affinities and modes. The docking results showed that the binding affinity values ranged from − 6.5 to − 10.1 kcal/mol which confirms their resilience potency when compared with 6.0kcal/mol of isoniazid standard drug. However, ligands 2, 7, 22, 26, and 35 scored higher binding affinity values of − 9.60, − 9.80, − 10.10, − 10.00, and − 10.00 kcal/mol, and are respectively considered as the best ligands among others with better binding modes in the active site of the modeled QcrB protein. Conclusion The information derived in this research revealed some potential hits and paved a route for structure-based drug discovery of new hypothetical imidazo pyridine amide analogs as anti-tubercular drug candidates.

Download Full-text

New Acylglycosides Flavones from Fuzhuan Brick Tea and Simulation Analysis of Their Bioactive Effects

International Journal of Molecular Sciences ◽

10.3390/ijms20030494 ◽

2019 ◽

Vol 20 (3) ◽

pp. 494 ◽

Cited By ~ 7

Author(s):

Ying Lu ◽

Yingjie He ◽

Shihao Zhu ◽

Xiaohong Zhong ◽

Dong Chen ◽

...

Keyword(s):

Simulation Analysis ◽

Docking Simulation ◽

Fragmentation Pathway ◽

Research Directions ◽

Hmg Coa Reductase ◽

Molecular Docking Simulation ◽

Chemical Structures ◽

Inhibitory Activities ◽

Coa Reductase ◽

Tof Ms

Four novel acylglycosides flavones (AGFs) including two quercetin acylglycosides and two kaempferol acylglycosides were isolated from Fuzhuan brick tea (FBT) as follows: quercetin 3-O-[α-l-rhamnopyranosyl (1→3)] [2-O’’-(E)-p-coumaroyl] [β-d-glucopyranosyl (1→3)-α-l-rhamnopyranosyl (1→6)]-β-d-galactoside was named as camelliquercetiside E (1), quercetin 3-O-[α-l-rhamnopyranosyl (1→3)] [2-O’’-(E)-p-coumaroyl] [α-l-rhamnopyranosyl (1→6)]-β-d-galactoside was named as camelliquercetiside F (2), kaempferol 3-O-[α-l-arabinopyranosyl (1→3)] [2-O’’-(E)-p-coumaroyl] [β-d-glucopyranosyl (1→3)-α-l-rhamnopyranosyl (1→6)]-β-d-glucoside was named as camellikaempferoside D (3), kaempferol 3-O-[α-l-arabinopyranosyl (1→3)] [2-O’’-(E)-p-coumaroyl] [α-l-rhamnopyranosyl (1→6)]-β-d-glucoside was named as camellikaempferoside E (4). Chemical structures of AGFs were identified by time-of-flight mass (TOF-MS) and NMR spectrometers (1H NMR, 13C NMR, 1H-1H COSY, HMBC and HSQC), and the MS2 fragmentation pathway of AGFs was further investigated. The inhibitory abilities of AGFs and their proposed metabolites on α-glucosidase and HMG-CoA reductase were analyzed by molecular docking simulation, and the results suggested that inhibitory activities of AGFs were significantly affected by acyl structure, number of glycosyl and conformation, and part of them had strong inhibitory activities on α-glucosidase and HMG-CoA reductase, suggesting that AGFs and their metabolites might be important ingredients that participate in the regulation of hypoglycemic and hypolipidemic effects. The results provided new AGFs and research directions for the practical study of FBT health functions in future.

Download Full-text

Unveiling novel inhibitors of dopamine transporter via in silico drug design, molecular docking, and bioavailability predictions as potential antischizophrenic agents

Future Journal of Pharmaceutical Sciences ◽

10.1186/s43094-021-00198-3 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Sabitu Babatunde Olasupo ◽

Adamu Uzairu ◽

Gideon Adamu Shallangwa ◽

Sani Uba

Keyword(s):

Molecular Docking ◽

Drug Design ◽

Binding Affinity ◽

Dopamine Transporter ◽

Hydrophobic Interactions ◽

Docking Simulation ◽

Experimental Investigations ◽

Template Molecule ◽

Molecular Docking Simulation ◽

Drug Candidates

Abstract Background The inhibition of dopamine transporter is known to play a significant role in the treatment of schizophrenia-related and other mental disorders. In a continuing from our previous study, computational drug design approach, molecular docking simulation, and pharmacokinetics study were explored for the identification of novel inhibitors dopamine transporter as potential Antischizophrenic agents. Consequently, thirteen (13) new inhibitors of dopamine transporter were designed by selecting the molecule with serial number 39 from our previous study as the template molecule because it exhibits good pharmacological attributes. Results Molecular docking simulation results revealed excellent molecular interactions between the protein target (PDB: 4m48) and the ligands (designed inhibitors) with major interactions that involved hydrogen bonding and hydrophobic interactions. Also, some of the designed inhibitors displayed a superior binding affinity range from − 10.0 to − 10.7 kcal/mol compared to the referenced drug (Lumateperone) with a binding affinity of − 9.7 kcal/mol. Computed physicochemical parameters showed that none of the designed inhibitors including the referenced drug violate Lipinski’s rule of five indicating that all the designed inhibitors would be orally bioavailable as potential drug candidates. Similarly, the ADMET/pharmacokinetics evaluations of some designed inhibitors revealed that they possessed good absorption, distribution, metabolism and excretion properties and none of the inhibitors is neither carcinogens nor toxic toward human ether-a-go-go related gene (hERG I) inhibitor or skin sensitization. Likewise, the BOILED-Egg graphics unveils that all the designed inhibitors demonstrate a high probability to be absorbed by the human gastrointestinal tract and could permeate into the brain. Besides, the predicted bioactive parameters suggested that all the selected inhibitors would be active as drug candidates. Furthermore, the synthetic accessibility scores for all the selected inhibitors and referenced drug lied within the easy zone (i.e., between 1–4) with their computed values range from 2.55 to 3.92, this implies that all the selected inhibitors would be very easy to synthesize in the laboratory. Conclusions Hence, all the designed inhibitors having shown excellent pharmacokinetics properties and good bioavailabilities attributes with remarkable biochemical interactions could be developed and optimized as novel Antischizophrenic agents after the conclusion of other experimental investigations.

Download Full-text

Selective Inhibition of Human Monoamine Oxidase B by 5-hydroxy-2-methyl-chroman-4-one Isolated from an Endogenous Lichen Fungus Daldinia fissa

Journal of Fungi ◽

10.3390/jof7020084 ◽

2021 ◽

Vol 7 (2) ◽

pp. 84

Author(s):

Geum-Seok Jeong ◽

Myung-Gyun Kang ◽

Sang-Ah Han ◽

Ji-In Noh ◽

Jong-Eun Park ◽

...

Keyword(s):

Docking Simulation ◽

Selective Inhibition ◽

Competitive Inhibitor ◽

Selective Inhibitor ◽

Hydrogen Bond Interaction ◽

Mao B ◽

Brain Barrier Permeability ◽

Mao A ◽

Inhibitory Activities ◽

Lichen Fungus

Inhibitory activities against monoamine oxidases (MAOs) and cholinesterases (ChEs) and antioxidant activity were evaluated for 195 extracts from Ukraine-derived endogenous lichen fungi (ELF). Among them, an ELF13 (identified as Daldinia fissa) extract showed the highest inhibitory activity against MAO-B, and 5-hydroxy-2-methyl-chroman-4-one (HMC) was isolated as a ~ 4-fold selective inhibitor of MAO-B (IC50 = 3.23 µM) compared to MAO-A (IC50 = 13.97 µM). HMC is a reversible competitive inhibitor with a Ki value of 0.896 µM. No cytotoxicity was observed in normal and cancer cells at 50 µM of HMC. HMC showed blood–brain barrier permeability and high gastrointestinal absorption in silico pharmacokinetics. The docking simulation results showed that the binding affinity of HMC for MAO-B (−7.3 kcal/mol) was higher than that of MAO-A (−6.1 kcal/mol) and that HMC formed a hydrogen bond interaction with Cys172 of MAO-B (distance: 3.656 Å), whereas no hydrogen bonding was predicted with MAO-A. These results suggest that HMC can be considered a candidate for the treatment of neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease.

Download Full-text

Evaluation of the Inhibitory Activities of Ferula gummosa Bioactive Compounds against the Druggable Targets of SARS-CoV-2: Molecular Docking Simulation

Biointerface Research in Applied Chemistry ◽

10.33263/briac125.63826392 ◽

2021 ◽

Vol 12 (5) ◽

pp. 6382-6392

Keyword(s):

Molecular Docking ◽

Binding Sites ◽

Docking Simulation ◽

Large Family ◽

Viral Disease ◽

Valuable Resource ◽

Molecular Docking Simulation ◽

Natural Components ◽

Inhibitory Activities ◽

Druggable Targets

SARS-CoV-2, an infectious disease caused by a novel strain that belongs to a large family of coronaviruses, has emerged as a global health threat. This viral disease affects the epithelial cells of the respiratory system and eventually leads to pneumonia. Using medicine derived from natural and safe herbs could be an alternative way of preventing or even treating severe respiratory disorders. This research has been conducted to evaluate the anti-inflammatory potential of Ferula gummosa Boiss. in preventing Covid-19. Molecular docking simulation was performed on the 18 components of Ferula gummosa against known active binding sites of SARS-CoV-2. The results revealed that these compounds inhibited the vital proteins of SARS-CoV-2, including 6LU7, 6EX1, 6W9C, and 6M71. According to the docking scores (DS) and inhibition constants (Ki), the most potent anti-coronavirus activity is expressed in the order: Δ-Cadinen > β-eudesmol > Bulnesol. The docking results revealed that the natural components of Ferula gummosa, mainly Δ-Cadinene, could be considered a valuable resource for preventing the infection of SARS-CoV-2.

Download Full-text