scholarly journals Evaluation of the Isoflavone Genistein as Reversible Human Monoamine Oxidase-A and -B Inhibitor

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Najla O. Zarmouh ◽  
Samia S. Messeha ◽  
Faisel M. Elshami ◽  
Karam F. A. Soliman
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Therapeutic Agent ◽  
Docking Studies ◽  
Monoamine Oxidase A ◽  
Inhibition Kinetics ◽  
Mao B ◽  
Therapeutic Drugs ◽  
Mao A ◽  
Luminescence Assay

Monoamine oxidases inhibitors (MAOIs) are effective therapeutic drugs for managing Parkinson’s disease (PD) and depression. However, their irreversibility may lead to rare but serious side effects. As finding safer and reversible MAOIs is our target, we characterized therecombinant human(h) MAO-A and MAO-B inhibition potentials of two common natural isoflavones, genistein (GST) and daidzein (DZ) using luminescence assay. The results obtained showed that DZ exhibits partial to no inhibition of the isozymes examined while GST inhibitedhMAO-B (IC50of 6.81 μM), and itshMAO-A inhibition was more potent than the standard deprenyl. Furthermore, the reversibility, mode of inhibition kinetics, and tyramine oxidation of GST were examined. GST was a time-independent reversible and competitivehMAO-A andhMAO-B inhibitor with a lowerKiofhMAO-B (1.45 μM) thanhMAO-A (4.31 μM). GST also inhibitedhMAO-B tyramine oxidation and hydrogen peroxide production more thanhMAO-A. Docking studies conducted indicated that the GST reversibility andhMAO-B selectivity of inhibition may relate to C5-OH effects on its orientation and its interactions with the threonine 201 residue of the active site. It was concluded from this study that the natural product GST has competitive and reversible MAOs inhibitions and may be recommended for further investigations as a useful therapeutic agent for Parkinson’s disease.

scholarly journals Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5358
Author(s):  
Narayan D. Chaurasiya ◽  
Jacob Midiwo ◽  
Pankaj Pandey ◽  
Regina N. Bwire ◽  
Robert J. Doerksen ◽  
...  
Keyword(s):  
Natural Products ◽  
Enzyme Inhibition ◽  
Selective Inhibition ◽  
Monoamine Oxidase A ◽  
Inhibition Kinetics ◽  
Free Energies ◽  
Mao B ◽  
Mao A ◽  
Enzyme Inhibition Kinetics ◽  
Binding Free Energies

A set of structurally related O-methylated flavonoid natural products isolated from Senecio roseiflorus (1), Polygonum senegalense (2 and 3), Bhaphia macrocalyx (4), Gardenia ternifolia (5), and Psiadia punctulata (6) plant species were characterized for their interaction with human monoamine oxidases (MAO-A and -B) in vitro. Compounds 1, 2, and 5 showed selective inhibition of MAO-A, while 4 and 6 showed selective inhibition of MAO-B. Compound 3 showed ~2-fold selectivity towards inhibition of MAO-A. Binding of compounds 1–3 and 5 with MAO-A, and compounds 3 and 6 with MAO-B was reversible and not time-independent. The analysis of enzyme-inhibition kinetics suggested a reversible-competitive mechanism for inhibition of MAO-A by 1 and 3, while a partially-reversible mixed-type inhibition by 5. Similarly, enzyme inhibition-kinetics analysis with compounds 3, 4, and 6, suggested a competitive reversible inhibition of MAO-B. The molecular docking study suggested that 1 selectively interacts with the active-site of human MAO-A near N5 of FAD. The calculated binding free energies of the O-methylated flavonoids (1 and 4–6) and chalcones (2 and 3) to MAO-A matched closely with the trend in the experimental IC50′s. Analysis of the binding free-energies suggested better interaction of 4 and 6 with MAO-B than with MAO-A. The natural O-methylated flavonoid (1) with highly potent inhibition (IC50 33 nM; Ki 37.9 nM) and >292 fold selectivity against human MAO-A (vs. MAO-B) provides a new drug lead for the treatment of neurological disorders.

Identification of Novel Phyto-chemicals from Ocimum basilicum for the Treatment of Parkinson’s Disease using In Silico Approach

2020 ◽  
Vol 16 (4) ◽  
pp. 420-434
Author(s):  
Nageen Mubashir ◽  
Rida Fatima ◽  
Sadaf Naeem
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Docking ◽  
Virtual Screening ◽  
Active Site ◽  
In Silico ◽  
Chemical Constituents ◽  
Docking Studies ◽  
Ocimum Basilicum ◽  
Mao B

Background: Parkinson’s disease is characterized by decreased level of dopaminergic neurotransmitters and this decrease is due to the degradation of dopamine by protein Monoamine Oxidase B (MAO-B). In order to treat Parkinson’s disease, MAO-B should be inhibited. Objective: To find out the novel phytochemicals from plant Ocimum basilicum that can inhibit MAO-B by using the in silico methods. Methods: The data of chemical constituents from plant Ocimum basilicum was collected and inhibitory activity of these phytochemicals was then predicted by using the Structure-Based (SB) and Ligand-Based Virtual Screening (LBVS) methods. Molecular docking, one of the common Structure-Based Virtual Screening method, has been used during this search. Traditionally, molecular docking is used to predict the orientation and binding affinity of the ligand within the active site of the protein. Molegro Virtual Docker (MVD) software has been used for this purpose. On the other hand, Random Forest Model, one of the LBVS method, has also been used to predict the activity of these chemical constituents of Ocimum basilicum against the MAO-B. Results: During the docking studies, all the 108 compounds found in Ocimum basilicum were docked within the active site of MAO-B (PDB code: 4A79) out of which, 57 compounds successfully formed the hydrogen bond with tyr 435, a crucial amino acid for the biological activity of the enzyme. Rutin (-182.976 Kcal/mol), Luteolin (-163.171 Kcal/mol), Eriodictyol-7-O-glucoside (- 160.13 Kcal/mol), Rosmarinic acid (-133.484 Kcal/mol) and Isoquercitrin (-131.493 Kcal/mol) are among the top hits with the highest MolDock score along with hydrogen interaction with tyr 435. Using the RF model, ten compounds out of 108 chemical constituent of Ocimum basilicum were predicted to be active, Apigenin (1.0), Eriodictyol (1.0), Orientin (0.876), Kaempferol (0.8536), Luteolin (0.813953) and Rosmarinic-Acid (0.7738095) are predicted to be most active with the highest RF score. Conclusion: The comparison of the two screening methods show that the ten compounds that were predicted to be active by the RF model, are also found in top hits of docking studies with the highest score. The top hits obtained during this study are predicted to be the inhibitor of MAO-B, thus, could be used further for the development of drugs for the treatment of Parkinson’s disease (PD).

Monoamineoxidase-B (MAO-B) Inhibitors in theTreatment of Alzheimer’s and Parkinson’s Disease

2021 ◽  
Vol 28 ◽  
Author(s):  
Zeynep Özdemir ◽  
Mehmet Abdullah Alagöz ◽  
Ömer Faruk Bahçecioğlu ◽  
Selim Gök
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Qualitative Content Analysis ◽  
The Elderly ◽  
Dimensional Structure ◽  
Peripheral Tissues ◽  
Mao B ◽  
Mao A

Background: The MAO enzyme which is presented in the brain and peripheral tissues and is a significant enzyme that is responsible for the deamination of biogenic amines and thus regulation of neurotransmitter levels. The reaction of these neurotransmitters with MAO enzyme produces aldehyde and free amine. MAO enzyme consists of two isoforms, MAO-A and MAO-B, which are characterized by amino acid sequence, three-dimensional structure, substrate preference and inhibitor selectivity. Dopamine, tyramine, and tryptamine are substrates of both MAO isoforms and MAO inhibitors such as clorgiline, selegiline that are used as medications in neurodegenerative and neurological diseases. In particular, MAO-A inhibitors are used in the treatment of depression, while MAO-B inhibitors are used in the treatment of Parkinson's disease. It is also investigated whether MAO-B inhibitors are effective in the treatment of Alzheimer's disease. Nowadays, life expectancy has increased; as a result, neurodegenerative diseases such as Parkinson's and Alzheimer's disease have started to seen more frequently. The elderly population is increasing day by day. As a result of these common diseases in the elderly people, these people are unable to do their jobs and need care. Therefore, these diseases have become a significant health problem in society. Methods: In this study, review, inclusion and exclusion criteria were used. Research articles with peer-reviewed were searched. The quality of the examined articles was evaluated with standard tools. The information obtained was analyzed conceptually by using qualitative content analysis methodology. Results: One hundred and five papers were included in the review. The current MAO-B inhibitors and their usage areas are discussed together with the structures of the drugs; also, their possible effects in Alzheimer’s and Parkinson’s treatment are evaluated. In addition, different articles have been compiled in which structures such as arylalkylamines, chalcones, benzoquinone, benzoxazinone, chromen are substituted with various functional groups and aromatic rings, and structures of 44 different compounds that have recently been developed and their inhibitory effects on MAO-B enzyme. As a result, the structure required for MAO-B inhibition and SAR studies are discussed and the literature was shed light. Conclusion: Many studies demonstrate that MAO-B activity increases with age in brain tissue, cerebrospinal fluid (CSF), and platelets in Alzheimer's patients. This suggests that MAO-B inhibitor drugs, which may be effective in the treatment of Parkinson's disease, may also be effective in the treatment of Alzheimer's disease. This article was written to explain the multifaceted MAO-B inhibitor molecules.

scholarly journals VIRTUAL SCREENING OF GINKGO BILOBA FOR THERAPEUTIC POTENTIALS AGAINST PARKINSON’S DISEASE

2016 ◽  
Vol 3 (1) ◽  
pp. 6-11
Author(s):  
Kavitha V ◽  
Jone Kirubavathy S ◽  
Sivaramkumar M.S ◽  
Velmurugan R
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Docking ◽  
Monoamine Oxidase ◽  
Ginkgo Biloba ◽  
Neurodegenerative Disorder ◽  
Docking Studies ◽  
Monoamine Oxidase B ◽  
Mao B ◽  
The Brain

Parkinson's disease (PD) is a neurodegenerative disorder that affects 2% of the population older than 60 years. Monoamine Oxidase B (MAO-B) inhibitors improve the symptoms of Parkinson's disease and can delay the progress. Inhibition of MAO-B, further prevent breakdown of dopamine in the brain and reducethe motor symptoms associated with PD. Ginkgo biloba has a number of therapeutic properties and contains phytonutrients that helps in improvement of neurological disorders. In present study, phytonutrients of Ginkgo biloba namely Myricetin, Quercetin, Isorhamnetin, Kaempferol, Ginkgolides A-C, and Ginkgolide J were selected for Molecular docking against Monoamine Oxidase-B enzyme. The Molecular Docking studies were performed using Autodock 4.2 and interaction between MAO-B and compounds were analyzed. The efficiency of the compound was screened based on the binding energy existing between the protein and inhibitor. The docking studies show that the phytochemicals of Ginkgo biloba against MAO-B were quite effective. The potential compound can be subjected to further clinical trials and can be an alternative in the future treatment of Parkinson’s disease.

scholarly journals Molecular docking of fisetin as a multi-target drug in the treatment of Parkinson’s disease

2019 ◽  
Vol 9 (1-s) ◽  
pp. 1-4
Author(s):  
Rajendran Malathi ◽  
K Prashanthi ◽  
J. Karthikeyan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Docking ◽  
Tyrosine Hydroxylase ◽  
Binding Energy ◽  
Molecular Interaction ◽  
Drug Targets ◽  
Neuroprotective Effect ◽  
Mao B ◽  
Mao A

Fisetin is found in various fruits and vegetables. It is reported to have neurotropic, anti-inflammatory, anti-carcinogenic and also other health benefits. Fisetin has been proved to have neuroprotective effect against Parkinson’s disease (PD).  Elucidation of the molecular interaction of fisetin with various anti-parkinsonian drug targets leads to better understanding mode of action of the drug. The present study is aimed to study the molecular interaction of fisetin with molecular targets having potential role in PD. The molecular properties and drug likeness model score were first analysed for flavonoid fisetin, which was found to be 0.76. The structures of the molecular drug targets, such as MAO A (2BXR), MAO B (2BYB), COMT (2AVD) and tyrosine hydroxylase (2XSN), was extracted from RCSB-Protein Data Bank. Molecular docking was performed using AUTO DOCK-4.2. The docking scores were evaluated by analyzing the minimum binding energy for the first five runs for all the target proteins. The minimum binding energy for MAO A (2BXR), MAO B (2BYB), COMT (2AVD), tyrosine hydroxylase (2XSN) were -10.22 kcal/mol, -9.68 kcal/mol, -7.45 kcal/mol and -6.67 kcal/mol respectively. Out of the 4 potential PD drug targets, MAO A and MAO, genes responsible for oxidative deamination of dopamine, are predicted to have the least minimum binding energy and best interaction with fisetin. Keywords: Fisetin, docking, multidrug targets, autodock, MAO A, MAO B, COMT, Tyrosine hydroxylase

A New Series Of 1,3-Dimethylxanthine Based Adenosine A2a Receptor Antagonists As A Non-Dopaminergic Treatment Of Parkinson’s Disease

2020 ◽  
Vol 17 ◽  
Author(s):  
Suman Rohilla ◽  
Ranju Bansal ◽  
Puneet Chauhan ◽  
Sonja Kachler ◽  
Karl-Norbert Klotz
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Docking ◽  
Binding Affinity ◽  
Docking Studies ◽  
Binding Modes ◽  
Molecular Docking Studies ◽  
In Silico Docking ◽  
Adenosine A2a Receptor Antagonists ◽  
The Impact

Background: Adenosine receptors (AR) have emerged as competent and innovative nondopaminergic targets for the development of potential drug candidates and thus constitute an effective and safer treatment approach for Parkinson’s disease (PD). Xanthine derivatives are considered as potential candidates for the treatment Parkinson’s disease due to their potent A2A AR antagonistic properties. Objective: The objectives of the work are to study the impact of substituting N7-position of 8-m/pchloropropoxyphenylxanthine structure on in vitro binding affinity of compounds with various AR subtypes, in vivo antiparkinsonian activity and binding modes of newly synthesized xanthines with A2A AR in molecular docking studies. Methods: Several new 7-substituted 8-m/p-chloropropoxyphenylxanthine analogues have been prepared. Adenosine receptor binding assays were performed to study the binding interactions with various subtypes and perphenazine induced rat catatonia model was used for antiparkinsonian activity. Molecular docking studies were performed using Schrödinger molecular modeling interface. Results: 8-para-substituted xanthine 9b bearing an N7-propyl substituent displayed the highest affinity towards A2A AR (Ki = 0.75 µM) with moderate selectivity versus other AR subtypes. 7-Propargyl analogue 9d produced significantly longlasting antiparkinsonian effects and also produced potent and selective binding affinity towards A2A AR. In silico docking studies further highlighted the crucial structural components required to develop xanthine derived potential A2A AR ligands as antiparkinsonian agents. Conclusion: A new series of 7-substituted 8-m/p-chloropropoxyphenylxanthines having good affinity for A2A AR and potent antiparkinsonian activity has been developed.

scholarly journals TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease

2017 ◽  
Vol 114 (40) ◽  
pp. 10773-10778 ◽  
Author(s):  
Seong Su Kang ◽  
Zhentao Zhang ◽  
Xia Liu ◽  
Fredric P. Manfredsson ◽  
Matthew J. Benskey ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Death ◽  
Kinase Domain ◽  
Alpha Synuclein ◽  
Mao B ◽  
Protein Levels ◽  
Trkb Receptors ◽  
Alpha Synuclein Aggregation ◽  
Neurotrophic Signaling

BDNF/TrkB neurotrophic signaling is essential for dopaminergic neuronal survival, and the activities are reduced in the substantial nigra (SN) of Parkinson’s disease (PD). However, whether α-Syn (alpha-synuclein) aggregation, a hallmark in the remaining SN neurons in PD, accounts for the neurotrophic inhibition remains elusive. Here we show that α-Syn selectively interacts with TrkB receptors and inhibits BDNF/TrkB signaling, leading to dopaminergic neuronal death. α-Syn binds to the kinase domain on TrkB, which is negatively regulated by BDNF or Fyn tyrosine kinase. Interestingly, α-Syn represses TrkB lipid raft distribution, decreases its internalization, and reduces its axonal trafficking. Moreover, α-Syn also reduces TrkB protein levels via up-regulation of TrkB ubiquitination. Remarkably, dopamine’s metabolite 3,4-Dihydroxyphenylacetaldehyde (DOPAL) stimulates the interaction between α-Syn and TrkB. Accordingly, MAO-B inhibitor rasagiline disrupts α-Syn/TrkB complex and rescues TrkB neurotrophic signaling, preventing α-Syn–induced dopaminergic neuronal death and restoring motor functions. Hence, our findings demonstrate a noble pathological role of α-Syn in antagonizing neurotrophic signaling, providing a molecular mechanism that accounts for its neurotoxicity in PD.

scholarly journals Effect of Harmine against Parkinson’s Disease Protein (PARK7) through Molecular Docking Studies

2021 ◽  
Vol 9 (VI) ◽  
pp. 5479-5485
Author(s):  
Love Kumar
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Docking ◽  
Neurodegenerative Disorder ◽  
Docking Studies ◽  
In Vivo Studies ◽  
Receptor Protein ◽  
Unknown Etiology

Parkinson’s disease (PD) is a common known neurodegenerative disorder with unknown etiology. It was estimated about 0.3% prevalence in the U.S population and enhance to 4 to 5% in older than 85 years. All studies were depending on the molecular docking where all ligands and protein PARK7 (PDB ID: 2RK3) were interacted by docked process. Some natural compounds was selected such as Harmine, Alloxan, Alpha spinasterol, Myrcene, and Vasicinone and PARK7 (PDB ID: 2RK3) protein. According to the PyRx and SWISS ADME result, Harmine was the only ligand which was showing minimum binding affinity. AutoDock Vina software was used for docking process between ligand (Harmine) and receptor protein PARK7 (PDB ID: 2RK3). The result was visualized under PyMol. Harmine was inhibiting the activity of PARK7 (PDB ID: 2RK3) and it may be used for the treatment of PD in future prospect after its in vitro and in vivo studies.

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