Parameters for Irreversible Inactivation of Monoamine Oxidase

The irreversible inhibitors of monoamine oxidases (MAO) slow neurotransmitter metabolism in depression and neurodegenerative diseases. After oxidation by MAO, hydrazines, cyclopropylamines and propargylamines form a covalent adduct with the flavin cofactor. To assist the design of new compounds to combat neurodegeneration, we have updated the kinetic parameters defining the interaction of these established drugs with human MAO-A and MAO-B and analyzed the required features. The Ki values for binding to MAO-A and molecular models show that selectivity is determined by the initial reversible binding. Common to all the irreversible inhibitor classes, the non-covalent 3D-chemical interactions depend on a H-bond donor and hydrophobic-aromatic features within 5.7 angstroms apart and an ionizable amine. Increasing hydrophobic interactions with the aromatic cage through aryl halogenation is important for stabilizing ligands in the binding site for transformation. Good and poor inactivators were investigated using visible spectroscopy and molecular dynamics. The initial binding, close and correctly oriented to the FAD, is important for the oxidation, specifically at the carbon adjacent to the propargyl group. The molecular dynamics study also provides evidence that retention of the allenyl imine product oriented towards FADH− influences the formation of the covalent adduct essential for effective inactivation of MAO.

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Interactions of Desmethoxyyangonin, a Secondary Metabolite fromRenealmia alpinia, with Human Monoamine Oxidase-A and Oxidase-B

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/4018724 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Narayan D. Chaurasiya ◽

Francisco León ◽

Yuanqing Ding ◽

Isabel Gómez-Betancur ◽

Dora Benjumea ◽

...

Keyword(s):

Enzyme Inhibitor ◽

Equilibrium Dialysis ◽

Monoamine Oxidase A ◽

Tropical Rainforests ◽

Reversible Binding ◽

Mao B ◽

Potent Inhibition ◽

Mao A ◽

Preferential Binding ◽

Phytochemical Studies

Renealmia alpinia(Zingiberaceae), a medicinal plant of tropical rainforests, is used to treat snakebites and other injuries and also as a febrifuge, analgesic, antiemetic, antiulcer, and anticonvulsant. The dichloromethane extract ofR. alpinialeaves showed potent inhibition of human monoamine oxidases- (MAOs-) A and B. Phytochemical studies yielded six known compounds, including pinostrobin1, 4′-methyl ether sakuranetin2, sakuranetin3, pinostrobin chalcone4, yashabushidiol A5, and desmethoxyyangonin6. Compound6displayed about 30-fold higher affinity for MAO-B than MAO-A, with Ki values of 31 and 922 nM, respectively. Kinetic analysis of inhibition and equilibrium-dialysis dissociation assay of the enzyme-inhibitor complex showed reversible binding of desmethoxyyangonin6with MAO-A and MAO-B. The binding interactions of compound6in the active site of the MAO-A and MAO-B isoenzymes, investigated through molecular modeling algorithms, confirmed preferential binding of desmethoxyyangonin6with MAO-B compared to MAO-A. Selective reversible inhibitors of MAO-B, like desmethoxyyangonin6,may have important therapeutic significance for the treatment of neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s disease.

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

Current Pharmaceutical Design ◽

10.2174/1381612827666210226123240 ◽

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.

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Molecular Basis of Iterative C–H Oxidation by TamI, a Multifunctional P450 Monooxygenase from the Tirandamycin Biosynthetic Pathway

10.26434/chemrxiv.12710159.v1 ◽

2020 ◽

Author(s):

Sean A. Newmister ◽

Kinshuk Raj Srivastava ◽

Rosa V. Espinoza ◽

Kersti Caddell Haatveit ◽

Yogan Khatri ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Molecular Basis ◽

Hydrophobic Interactions ◽

Cytochromes P450 ◽

Targeted Mutagenesis ◽

P450 Monooxygenase ◽

Bond Functionalization ◽

Dynamics Simulations

Biocatalysis offers an expanding and powerful strategy to construct and diversify complex molecules by C-H bond functionalization. Due to their high selectivity, enzymes have become an essential tool for C-H bond functionalization and offer complementary reactivity to small-molecule catalysts. Hemoproteins, particularly cytochromes P450, have proven effective for selective oxidation of unactivated C-H bonds. Previously, we reported the in vitro characterization of an oxidative tailoring cascade in which TamI, a multifunctional P450 functions co-dependently with the TamL flavoprotein to catalyze regio- and stereoselective hydroxylations and epoxidation to yield tirandamycin A and tirandamycin B. TamI follows a defined order including 1) C10 hydroxylation, 2) C11/C12 epoxidation, and 3) C18 hydroxylation. Here we present a structural, biochemical, and computational investigation of TamI to understand the molecular basis of its substrate binding, diverse reactivity, and specific reaction sequence. The crystal structure of TamI in complex with tirandamycin C together with molecular dynamics simulations and targeted mutagenesis suggest that hydrophobic interactions with the polyene chain of its natural substrate are critical for molecular recognition. QM/MM calculations and molecular dynamics simulations of TamI with variant substrates provided detailed information on the molecular basis of sequential reactivity, and pattern of regio- and stereo-selectivity in catalyzing the three-step oxidative cascade.<br>

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Faculty Opinions recommendation of Enhancement of hydrophobic interactions and hydrogen bond strength by cooperativity: synthesis, modeling, and molecular dynamics simulations of a congeneric series of thrombin inhibitors.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13372988.14743099 ◽

2011 ◽

Author(s):

Martin Stahl

Keyword(s):

Molecular Dynamics ◽

Hydrogen Bond ◽

Bond Strength ◽

Molecular Dynamics Simulations ◽

Hydrophobic Interactions ◽

Thrombin Inhibitors ◽

Hydrogen Bond Strength ◽

Dynamics Simulations

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

Molecules ◽

10.3390/molecules25173896 ◽

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.

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

Alternatives to Laboratory Animals ◽

10.1177/026119298901600313 ◽

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00431-13 ◽

2013 ◽

Vol 57 (7) ◽

pp. 3060-3066 ◽

Cited By ~ 61

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).

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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.

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