scholarly journals Demonstration of Isoleucine 199 as a Structural Determinant for the Selective Inhibition of Human Monoamine Oxidase B by Specific Reversible Inhibitors

2005 ◽  
Vol 280 (16) ◽  
pp. 15761-15766 ◽  
Author(s):  
Frantisek Hubálek ◽  
Claudia Binda ◽  
Ashraf Khalil ◽  
Min Li ◽  
Andrea Mattevi ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Selective Inhibition ◽  
Competitive Inhibitor ◽  
Side Chain ◽  
Monoamine Oxidase B ◽  
Sequence Alignments ◽  
Reversible Inhibitors ◽  
Mao B ◽  
Mao A ◽  
Structural Determinant

Several reversible inhibitors selective for human monoamine oxidase B (MAO B) that do not inhibit MAO A have been described in the literature. The following compounds: 8-(3-chlorostyryl)caffeine, 1,4-diphenyl-2-butene, andtrans,trans-farnesol are shown to inhibit competitively human, horse, rat, and mouse MAO B withKivalues in the low micromolar range but are without effect on either bovine or sheep MAO B or human MAO A. In contrast, the reversible competitive inhibitor isatin binds to all known MAO B and MAO A with similar affinities. Sequence alignments and the crystal structures of human MAO B in complex with 1,4-diphenyl-2-butene or withtrans,trans-farnesol provide molecular insights into these specificities. These inhibitors span the substrate and entrance cavities with the side chain of Ile-199 rotated out of its normal conformation suggesting that Ile-199 is gating the substrate cavity. Ile-199 is conserved in all known MAO B sequences except bovine MAO B, which has Phe in this position (the sequence of sheep MAO B is unknown). Phe is conserved in the analogous position in MAO A sequences. The human MAO B I199F mutant protein of MAO B binds to isatin (Ki= 3 μm) but not to the three inhibitors listed above. The crystal structure of this mutant demonstrates that the side chain of Phe-199 interferes with the binding of those compounds. This suggests that the Ile-199 “gate” is a determinant for the specificity of these MAO B inhibitors and provides a molecular basis for the development of MAO B-specific reversible inhibitors without interference with MAO A function in neurotransmitter metabolism.

scholarly journals Inhibition of Butyrylcholinesterase and Human Monoamine Oxidase-B by the Coumarin Glycyrol and Liquiritigenin Isolated from Glycyrrhiza uralensis

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 3896
Author(s):  
Geum Seok Jeong ◽  
Myung-Gyun Kang ◽  
Joon Yeop Lee ◽  
Sang Ryong Lee ◽  
Daeui Park ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Binding Affinity ◽  
Competitive Inhibitor ◽  
Glycyrrhiza Uralensis ◽  
Form Hydrogen Bond ◽  
Docking Simulations ◽  
Mao B ◽  
Mao A ◽  
Ic50 Values ◽  
Noncompetitive Inhibitor

Eight compounds were isolated from the roots of Glycyrrhiza uralensis and tested for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activities. The coumarin 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 (>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.

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

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.

Identification of butyrylcholinesterase and monoamine oxidase B targeted ligands and their putative application in Alzheimer’s treatment: A computational strategy

2021 ◽  
Vol 27 ◽  
Author(s):  
Nasimudeen R Jabir ◽  
Md Tabish Rehman ◽  
Shams Tabrez ◽  
Raed F. Alserihi ◽  
Mohamed F AlAjmi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Monoamine Oxidase ◽  
Monoamine Oxidase A ◽  
Dynamics Simulation ◽  
Stable Complex ◽  
Monoamine Oxidase B ◽  
Mao B ◽  
Computational Screening ◽  
Mao A

Background: With the burgeoning worldwide aging population, the incidence of Alzheimer’s disease (AD) and its associated disorders is continuously rising. To appraise other relevant drug targets that could lead to potent enzyme targeting, 13 previously predicted ligands (shown favorable binding with AChE (acetylcholinesterase) and GSK-3 (glycogen synthase kinase) were screened for targeting 3 different enzymes namely butyrylcholinesterase (BChE), monoamine oxidase A (MAO-A), and monoamine oxidase B (MAO-B) to possibly meet the unmet medical need of better AD treatment. Materials and Methods: The study utilized in silico screening of 13 ligands against BChE, MAO-A and MAO-B using PyRx-Python prescription 0.8. The visualization of active interaction of studied compounds with targeted proteins was performed by Discovery Studio 2020 (BIOVIA). Results: The computational screening of studied ligands revealed the docking energies in the range of -2.4 to -11.3 kcal/mol for all the studied enzymes. Among the 13 ligands, 8 ligands (55E, 6Z2, 6Z5, BRW, F1B, GVP, IQ6, and X37) showed the binding energies of ≤ -8.0 kcal/mol towards BChE, MAO-A and MAO-B. The ligand 6Z5 was found to be the most potent inhibitor of BChE and MAO-B, with a binding energy of -9.7 and -10.4 kcal mol respectively. Molecular dynamics simulation of BChE-6Z5 and MAO-B-6Z5 complex confirmed the formation of a stable complex. Conclusion: Our computational screening, molecular docking, and molecular dynamics simulation studies revealed that the above-mentioned enzymes targeted ligands might expedite the future design of potent anti-AD drugs generated on this chemical scaffold.

Development of Monoamine Oxidase and Aldehyde Dehydrogenase in Reaggregating Cultures of Fetal Rat Brain Cells

1989 ◽  
Vol 16 (3) ◽  
pp. 281-286
Author(s):  
Olof Tottmar ◽  
Maria Söderbäck ◽  
Anders Aspberg
Keyword(s):  
Monoamine Oxidase ◽  
Rat Brain ◽  
Aldehyde Dehydrogenase ◽  
Brain Cells ◽  
Mao B ◽  
Adult Rat ◽  
Fetal Rat ◽  
Adult Rat Brain ◽  
Mao A ◽  
Fetal Rat Brain

The development of monoamine oxidase (MAO) and aldehyde dehydrogenase (ALDH) in reaggregation cultures of fetal rat brain cells was compared with that of enzymatic markers for glial and neuronal cells. Only MAO-A was detected in the cultures during the first week, but, during the following three weeks, the activity of MAO-B increased more rapidly than that of MAO-A. The ratio MAO-A/MAO-B in four-week aggregates was close to that found in the adult rat brain. The activity of ALDH started to increase rapidly after 15 days, and the developmental pattern was intermediate to those of the glial and neuronal markers. The activity after four weeks was close to that found in the adult rat brain. Epidermal growth factor (EGF) caused a slight decrease in the activities of the low-Km ALDH (after four weeks) and the neuronal marker, choline acetyltransferase (after two weeks), whereas the other markers were not affected. By contrast, the activities of MAO-A and MAO-B were greatly increased during almost the entire culture period. It is suggested that this effect of EGF was the result of increased mitotic activity and/or biochemical differentiation of other cell types present in the cell aggregates, e.g. capillary endothelial cells.

scholarly journals 4-Phenethyl-1-Propargylpiperidine-Derived Dual Inhibitors of Butyrylcholinesterase and Monoamine Oxidase B

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4118
Author(s):  
Tjaša Mazej ◽  
Damijan Knez ◽  
Anže Meden ◽  
Stanislav Gobec ◽  
Matej Sova
Keyword(s):  
Monoamine Oxidase ◽  
Docking Studies ◽  
Monoamine Oxidase B ◽  
Mao B ◽  
Initial Expectation ◽  
Excellent Starting Point ◽  
Starting Point ◽  
Dependent Inhibition ◽  
Dual Inhibitors ◽  
Time Dependent Inhibition

The multi-target-directed ligands (MTDLs) strategy is encouraged for the development of novel modulators targeting multiple pathways in the neurodegenerative cascade typical for Alzheimer’s disease (AD). Based on the structure of an in-house irreversible monoamine oxidase B (MAO-B) inhibitor, we aimed to introduce a carbamate moiety on the aromatic ring to impart cholinesterase (ChE) inhibition, and to furnish multifunctional ligands targeting two enzymes that are intricately involved in AD pathobiology. In this study, we synthesized three dual hMAO-B/hBChE inhibitors 13–15, with compound 15 exhibiting balanced, low micromolar inhibition of hMAO-B (IC50 of 4.3 µM) and hBChE (IC50 of 8.5 µM). The docking studies and time-dependent inhibition of hBChE confirmed the initial expectation that the introduced carbamate moiety is responsible for covalent inhibition. Therefore, dual-acting compound 15 represents an excellent starting point for further optimization of balanced MTDLs.

scholarly journals In Vitro,In Vivo, and Clinical Studies of Tedizolid To Assess the Potential for Peripheral or Central Monoamine Oxidase Interactions

2013 ◽  
Vol 57 (7) ◽  
pp. 3060-3066 ◽  
Author(s):  
S. Flanagan ◽  
K. Bartizal ◽  
S. L. Minassian ◽  
E. Fang ◽  
P. Prokocimer
Keyword(s):  
Blood Pressure ◽  
Monoamine Oxidase ◽  
Clinical Research ◽  
Systolic Blood Pressure ◽  
Clinical Studies ◽  
Geometric Mean ◽  
Interaction Study ◽  
Mao B ◽  
Mao A

ABSTRACTTedizolid phosphate is a novel oxazolidinone prodrug whose active moiety, tedizolid, has improved potency against Gram-positive pathogens and pharmacokinetics, allowing once-daily administration. Given linezolid warnings for drug-drug and drug-food interactions mediated by monoamine oxidase (MAO) inhibition, including sporadic serotonergic toxicity, these studies evaluated tedizolid for potential MAO interactions.In vitro, tedizolid and linezolid were reversible inhibitors of human MAO-A and MAO-B; the 50% inhibitory concentration (IC50) for tedizolid was 8.7 μM for MAO-A and 5.7 μM for MAO-B and 46.0 and 2.1 μM, respectively, with linezolid. Tedizolid phosphate was negative in the mouse head twitch model of serotonergic activity. Two randomized placebo-controlled crossover clinical studies assessed the potential of 200 mg/day tedizolid phosphate (at steady state) to enhance pressor responses to coadministered oral tyramine or pseudoephedrine. Sensitivity to tyramine was determined by comparing the concentration of tyramine required to elicit a ≥30-mmHg increase in systolic blood pressure (TYR30) when administered with placebo versus tedizolid phosphate. The geometric mean tyramine sensitivity ratio (placebo TYR30/tedizolid phosphate TYR30) was 1.33; a ratio of ≥2 is considered clinically relevant. In the pseudoephedrine study, mean maximum systolic blood pressure was not significantly different when pseudoephedrine was coadministered with tedizolid phosphate versus placebo. In summary, tedizolid is a weak, reversible inhibitor of MAO-A and MAO-Bin vitro. Provocative testing in humans and animal models failed to uncover significant signals that would suggest potential for hypertensive or serotonergic adverse consequences at the therapeutic dose of tedizolid phosphate. Clinical studies are registered atwww.clinicaltrials.govas NCT01539473 (tyramine interaction study conducted at Covance Clinical Research Center, Evansville, IN) and NCT01577459 (pseudoephedrine interaction study conducted at Vince and Associates Clinical Research, Overland Park, KS).

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

Molecules ◽  
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.

scholarly journals Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1304
Author(s):  
Vedanjali Gogineni ◽  
Manal A. Nael ◽  
Narayan D. Chaurasiya ◽  
Khaled M. Elokely ◽  
Christopher R. McCurdy ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Methyl Ether ◽  
Neurological Disorders ◽  
Potential Application ◽  
Selectivity Index ◽  
Lead Optimization ◽  
Mao B ◽  
Reversible Inhibition ◽  
Mao A ◽  
Dietary Flavonoid

A series of dietary flavonoid acacetin 7-O-methyl ether derivatives were computationally designed aiming to improve the selectivity and potency profiles against monoamine oxidase (MAO) B. The designed compounds were evaluated for their potential to inhibit human MAO-A and -B. Compounds 1c, 2c, 3c, and 4c were the most potent with a Ki of 37 to 68 nM against MAO-B. Compounds 1c–4c displayed more than a thousand-fold selectivity index towards MAO-B compared with MAO-A. Moreover, compounds 1c and 2c showed reversible inhibition of MAO-B. These results provide a basis for further studies on the potential application of these modified flavonoids for the treatment of Parkinson’s Disease and other neurological disorders.

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