Three-dimensional structure of human monoamine oxidase A (MAO A): Relation to the structures of rat MAO A and human MAO B

The research of ligand-protein interactions with in silico molecular modeling studies on the atomic level gives an opportunity to be understood the pharmacokinetic metabolism of anti-depressant drug candidates. Monoamine oxidase (MAO) enzymes are important targets for the treatment of depressive disorder. MAOs have two isoforms as MAO-A and MAO-B being responsible for catalyzing of neurological amines. In this study a new series of coumarin derivatives were designed for selective and reversible inhibition of MAO-A enzyme. 3rd, 5th and 7th positions were selected to be placed of five different side groups. Docking procedures of each ligand in M series of these novel 125 compounds were executed with 10 runs by using AutoDock4.2 software. Docking results were analyzed via Discovery Studio 3.1 (Biovia Inc.). The most promising compounds were M118 and M123 according to selectivity index, SI (MAO-B/MAO-A)=180 fold and 209 fold and Ki values 7.25 nM and 12.01 nM, respectively. Overall, the current study provided significant knowledge for the development of new anti-depressant drugs.

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Isolation and Biological Evaluation of Prenylated Flavonoids from Maclura pomifera

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/1370368 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Yerkebulan Orazbekov ◽

Mohamed A. Ibrahim ◽

Serjan Mombekov ◽

Radhakrishnan Srivedavyasasri ◽

Ubaidilla Datkhayev ◽

...

Keyword(s):

Monoamine Oxidase ◽

Opioid Receptors ◽

Cannabinoid Receptors ◽

Biological Evaluation ◽

Monoamine Oxidase A ◽

Moderate Activity ◽

Significant Activity ◽

Mao B ◽

Maclura Pomifera ◽

Mao A

Phytochemical analysis of the ethanolic extract of Maclura pomifera fruits yielded four new compounds (I–IV) along with eleven known compounds (V–XV). The crude extract exhibited significant activity towards cannabinoid receptors (CB1: 103.4% displacement; CB2: 68.8% displacement) and possibly allosteric interaction with δ and μ opioid receptors (−49.7 and −53.8% displacement, resp.). Compound I was found to be possibly allosteric for κ and μ opioid receptors (−88.4 and −27.2% displacement, resp.) and showed moderate activity (60.5% displacement) towards CB1 receptor. Compound II exhibited moderate activity towards cannabinoid receptors CB1 and CB2 (47.9 and 42.3% displacement, resp.). The known compounds (V–VIII) exhibited prominent activity towards cannabinoid receptors: pomiferin (V) (IC50 of 2.110 and 1.318 μM for CB1 and CB2, resp.), auriculasin (VI) (IC50 of 8.923 μM for CB1), warangalone (VII) (IC50 of 1.670 and 4.438 μM for CB1 and CB2, resp.), and osajin (VIII) (IC50 of 3.859 and 7.646 μM for CB1 and CB2, resp.). The isolated compounds were also tested for inhibition of human monoamine oxidase-A and monoamine oxidase-B enzymes activities, where all the tested compounds showed fewer inhibitory effects on MAO-A compared to MAO-B activities: auriculasin (VI) (IC50 of 1.91 and 45.98 μM for MAO-B and MAO-A, resp.).

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Histochemical investigation of criteria for the distinction between monoamine oxidase A and B in various species.

Journal of Histochemistry & Cytochemistry ◽

10.1177/32.6.6202738 ◽

1984 ◽

Vol 32 (6) ◽

pp. 667-673 ◽

Cited By ~ 31

Author(s):

E Uchida ◽

G B Koelle

Keyword(s):

Dorsal Root Ganglion ◽

Monoamine Oxidase ◽

Dorsal Root ◽

Monoamine Oxidase A ◽

Rat Tissues ◽

Histochemical Investigation ◽

Mao B ◽

Total Inhibition ◽

Mao A ◽

Cervical Ganglion

The superior cervical ganglion (SCG), pineal body (PB), and liver (L) of the rat, rabbit and cat were stained for monoamine oxidase (MAO) A and B by the tetranitro blue tetrazolium (TNBT) and coupled peroxidase ( PerOx ) methods, using 5-hydroxytryptamine (5HT), tryptamine ( Tryp ), tyramine (Tyr), and benzylamine (Bz) as substrates, and clorgyline (Cl) and deprenyl (Dep), both at 10(-7) M, as selective inhibitors. The nodose ganglion (NG) and dorsal root ganglion (DRG) of the rabbit and cat were also studied. The results with rat tissues were consistent with published quantitative findings (SCG, MAO-A much greater than B; PB, MAO-A less than or equal to B; L, MAO-A = B). In the rabbit, the findings with the SCG were similar; the MAO activities of the PB were relatively resistant to both inhibitors; the MAO of the liver required 10(-4) M concentrations of both inhibitors to produce near total inhibition, suggesting that the liver contains an MAO distinct from MAO A and B. All cat tissues examined appeared to contain almost exclusively MAO-B. In this species 5HT, which is generally considered a selective substrate for MAO-A, was oxidized by MAO-B. The findings indicate that criteria for MAO-A, -B, and other subgroups must be defined for each species and tissue.

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Developing a Multi-target Model to Predict the Activity of Monoamine Oxidase A and B Drugs

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200603121224 ◽

2020 ◽

Vol 20 (18) ◽

pp. 1593-1600 ◽

Cited By ~ 2

Author(s):

Riccardo Concu ◽

Michael González-Durruthy ◽

Maria Natália D.S. Cordeiro

Keyword(s):

Side Effects ◽

Monoamine Oxidase ◽

Statistical Tests ◽

Qsar Model ◽

Monoamine Oxidase A ◽

Mao Inhibitors ◽

Computational Approaches ◽

Linear Discriminant ◽

Mao B ◽

Mao A

Introduction: Monoamine oxidase inhibitors (MAOIs) are compounds largely used in the treatment of Parkinson’s disease (PD), Alzheimer’s disease and other neuropsychiatric disorders since they are closely related to the MAO enzymes activity. The two isoforms of the MAO enzymes, MAO-A and MAO-B, are responsible for the degradation of monoamine neurotransmitters and due to this, relevant efforts have been devoted to finding new compounds with more selectivity and less side effects. One of the most used approaches is based on the use of computational approaches since they are time and money-saving and may allow us to find a more relevant structure-activity relationship. Objectives: In this manuscript, we will review the most relevant computational approaches aimed at the prediction and development of new MAO inhibitors. Subsequently, we will also introduce a new multitask model aimed at predicting MAO-A and MAO-B inhibitors. Methods: The QSAR multi-task model herein developed was based on the use of the linear discriminant analysis. This model was developed gathering 5,759 compounds from the public dataset Chembl. The molecular descriptors used was calculated using the Dragon software. Classical statistical tests were performed to check the validity and robustness of the model. Results: The herein proposed model is able to correctly classify all the 5,759 compounds. All the statistical performed tests indicated that this model is robust and reproducible. Conclusion: MAOIs are compounds of large interest since they are largely used in the treatment of very serious illness. These inhibitors may lose efficacy and produce severe side effects. Due to this, the development of selective MAO-A or MAO-B inhibitors is crucial for the treatment of these diseases and their effects. The herein proposed multi-target QSAR model may be a relevant tool in the development of new and more selective MAO inhibitors.

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Thyroid iodide transport is reduced by administration of monoamine oxidase A inhibitors to rats

Journal of Endocrinology ◽

10.1677/joe.0.1430303 ◽

1994 ◽

Vol 143 (2) ◽

pp. 303-308 ◽

Cited By ~ 6

Author(s):

A M Cabanillas ◽

A M Masini-Repiso ◽

M E Costamagna ◽

C Pellizas ◽

A H Coleoni

Keyword(s):

Monoamine Oxidase ◽

Transport Mechanism ◽

Monoamine Oxidase A ◽

Mao Inhibitors ◽

Iodide Uptake ◽

Mao B ◽

Iodide Transport ◽

Mao A ◽

Mao Activity

Abstract The present work was addressed to study a possible relationship between monoamine oxidase (MAO) and the thyroid iodide transport mechanism. Normal rats treated with clorgyline (a selective MAO-A inhibitor) or tranylcypromine (a non-selective MAO inhibitor) showed a significantly diminished thyroid MAO activity, while deprenyl and pargyline (MAO-B inhibitors) did not modify the thyroidal enzyme activity with respect to the control group. Under these conditions, in vivo iodide transport was reduced both by clorgyline and tranylcypromine administration whereas it remained unchanged after treatment with MAO-B inhibitors. The effect of MAO inhibitors on thyroid MAO activity and in vivo iodide transport was also evaluated in rats treated with exogenous thyrotrophin (TSH) after endogenous TSH secretion blockade produced by T4 administration. In this condition, thyroid MAO activity was significantly lowered by clorgyline and was not modified by deprenyl. In contrast to the results observed in normal rats, in vivo iodide transport in TSH-treated rats remained unaltered after treatment either with clorgyline or deprenyl. MAO activity evaluated in bovine thyroid follicles in primary culture was highly sensitive to low concentrations of clorgyline (<10 nmol/l) and relatively insensitive to deprenyl, a finding that indicates a predominance of the MAO-A isoform in the follicular cells in culture. When clorgyline (0·1 and 1 μmol/l) or deprenyl (1 μmol/l) were added to the culture medium, no modifications in the active transport of iodide were observed. These results indicate the absence of a direct linkage between thyroid MAO activity and the active iodide transport. MAO inhibitors (particularly MAO-A inhibitors) do not appear to be responsible for an in vivo diminished thyroid iodide uptake through a direct action on the iodide transport mechanism. An indirect effect of MAO-A inhibitors on thyroid iodide transport mediated by the accumulation of monoamines in neuroendocrine areas involved in TSH regulation is suggested. Journal of Endocrinology (1994) 143, 303–308

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Three Dimensional Pharmacophore Modelling of Monoamine oxidase-A (MAO-A) inhibitors

International Journal of Molecular Sciences ◽

10.3390/i8090894 ◽

2007 ◽

Vol 8 (9) ◽

pp. 894-919 ◽

Cited By ~ 1

Author(s):

Kalapatapu Sairam ◽

Roop Khar ◽

Rama Mukherjee ◽

Swatantra Jain

Keyword(s):

Monoamine Oxidase ◽

Three Dimensional ◽

Monoamine Oxidase A ◽

Pharmacophore Modelling ◽

Mao A

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Microbial Metabolite Urolithin B Inhibits Recombinant Human Monoamine Oxidase A Enzyme

Metabolites ◽

10.3390/metabo10060258 ◽

2020 ◽

Vol 10 (6) ◽

pp. 258

Author(s):

Rajbir Singh ◽

Sandeep Chandrashekharappa ◽

Praveen Kumar Vemula ◽

Bodduluri Haribabu ◽

Venkatakrishna Rao Jala

Keyword(s):

Monoamine Oxidase ◽

Enzyme Inhibitor ◽

Monoamine Oxidase A ◽

Mao B ◽

Functional Activities ◽

Mao A ◽

Mao Activity ◽

Anti Oxidant ◽

Urolithin B

Urolithins are gut microbial metabolites derived from ellagitannins (ET) and ellagic acid (EA), and shown to exhibit anticancer, anti-inflammatory, anti-microbial, anti-glycative and anti-oxidant activities. Similarly, the parent molecules, ET and EA are reported for their neuroprotection and antidepressant activities. Due to the poor bioavailability of ET and EA, the in vivo functional activities cannot be attributed exclusively to these compounds. Elevated monoamine oxidase (MAO) activities are responsible for the inactivation of monoamine neurotransmitters in neurological disorders, such as depression and Parkinson’s disease. In this study, we examined the inhibitory effects of urolithins (A, B and C) and EA on MAO activity using recombinant human MAO-A and MAO-B enzymes. Urolithin B was found to be a better MAO-A enzyme inhibitor among the tested urolithins and EA with an IC50 value of 0.88 µM, and displaying a mixed mode of inhibition. However, all tested compounds exhibited higher IC50 (>100 µM) for MAO-B enzyme.

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Selected aryl thiosemicarbazones as a new class of multi-targeted monoamine oxidase inhibitors

MedChemComm ◽

10.1039/c8md00399h ◽

2018 ◽

Vol 9 (11) ◽

pp. 1871-1881 ◽

Cited By ~ 12

Author(s):

Bijo Mathew ◽

Seung Cheol Baek ◽

Della Grace Thomas Parambi ◽

Jae Pil Lee ◽

Monu Joy ◽

...

Keyword(s):

Monoamine Oxidase ◽

Monoamine Oxidase Inhibitors ◽

Monoamine Oxidase A ◽

Mao B ◽

New Class ◽

Mao A ◽

Inhibitory Potential

A series of 13 phenyl substituted thiosemicarbazones (SB1–SB13) were synthesized and evaluated for their inhibitory potential towards human recombinant monoamine oxidase A and B (MAO-A and MAO-B, respectively) and acetylcholinesterase.

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The Antiproliferative Effects of Flavonoid MAO Inhibitors on Prostate Cancer Cells

Molecules ◽

10.3390/molecules25092257 ◽

2020 ◽

Vol 25 (9) ◽

pp. 2257 ◽

Cited By ~ 1

Author(s):

Najla O. Zarmouh ◽

Samia S. Messeha ◽

Nelly Mateeva ◽

Madhavi Gangapuram ◽

Kacy Flowers ◽

...

Keyword(s):

Prostate Cancer ◽

Molecular Docking ◽

Monoamine Oxidase ◽

Cell Lines ◽

Monoamine Oxidase A ◽

Hydroxyl Groups ◽

Antiproliferative Effects ◽

Mao B ◽

Chlorine Substitution ◽

Mao A

Prostate cancer (PCa) patients commonly experience clinical depression. Recent reports indicated that monoamine oxidase-A (MAO-A) levels elevate in PCa, and antidepressant MAO-Is show anti-PCa properties. In this work, we aimed to find potential drugs for PCa patients suffering from depression by establishing novel anti-PCa reversible monoamine oxidase-A inhibitors (MAO-AIs/RIMA); with an endeavor to understand their mechanism of action. In this investigation, twenty synthesized flavonoid derivatives, defined as KKR compounds were screened for their inhibitory potentials against human MAO-A and MAO-B isozymes. Meanwhile, the cytotoxic and antiproliferative effects were determined in three human PCa cell lines. MAO-A-kinetics, molecular docking, SAR, cell morphology, and cell migration were investigated for the most potent compounds. The screened KKRs inhibited MAO-A more potently than MAO-B, and non-toxically inhibited LNCaP cell proliferation more than the DU145 and PC3 cell lines, respectively. The results showed that the three top MAO-AI KKRs compounds (KKR11, KKR20, and KKR7 (IC50s 0.02–16 μM) overlapped with the top six antiproliferative KKRs against LNCaP (IC50s ~9.4 μM). While KKR21 (MAO-AI) and KKR2A (MAO-I) were ineffective against the PCa cells. Furthermore, KKR21 and KKR11 inhibited MAO-A competitively (Kis ≤ 7.4 nM). Molecular docking of the two compounds predicted shared hydrophobic and distinctive hydrophilic interactions—between the KKR molecule and MAO-A amino acid residues—to be responsible for their reversibility. The combined results and SAR observations indicated that the presence of specific active groups—such as chlorine and hydroxyl groups—are essential in certain MAO-AIs with anti-PCa effects. Additionally, MAO-A inhibition was found to be associated more with anti-PCa property than MAO-B. Distinctively, KKR11 [(E)-3-(3,4-dichlorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one] exhibited anti-metastatic effects on the DU145 cell line. The chlorine substitution groups might play vital roles in the KKR11 multiple actions. The obtained results indicated that the flavonoid derivative KKR11 could present a novel candidate for PCa patients with depression, through safe non-selective potent inhibition of MAOs.

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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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