The Design and Evaluation of a Novel Monoamine Oxidase B Inhibitor Through in Silico Approach

2019 ◽  
Vol 10 (02) ◽  
Author(s):  
Hasanain Abdulhameed Odhar ◽  
Safaa Muhsen Kareem ◽  
Mohammed Ridha A Alhaideri ◽  
Mohammed Abbas Hasan ◽  
Werner J Geldenhuys
Keyword(s):  
Monoamine Oxidase ◽  
In Silico ◽  
Neuroprotective Effect ◽  
Monoamine Oxidase B ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mao B ◽  
Age Related ◽  
Novel Scaffold

Parkinson’s disease is an age related neurodegenerative disease. Pioglitazone is a Peroxisome proliferator-activated receptor gamma agonist that has been shown to display a neuroprotective effect in parkinsonian models (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated mice). This effect was partially attributed to the ability of thiazolidinedione (TZD) moiety in Pioglitazone to selectively inhibit monoamine oxidase B (MAO-B) enzyme. In the current study, we screened several thiazolidine containing compounds against MAO-B enzyme both in silico and in vitro. Based on the resulted data and information from previous literatures, we were able to design a novel scaffold for MAO-B inhibitors. This scaffold (compound 5482440) was able to inhibit MAO-B enzyme with IC50 value of 1.447 μM. Structure-based virtual analysis showed that this compound was able to participate in water-bridge formation and obtain an extended conformation within MAO-B active site.

New role for crinamine as a potent, safe and selective inhibitor of human monoamine oxidase B: In vitro and in silico pharmacology and modeling

2020 ◽  
Vol 248 ◽  
pp. 112305 ◽  
Author(s):  
D. Naidoo ◽  
A. Roy ◽  
L. Poštová Slavětínská ◽  
J.C. Chukwujekwu ◽  
S. Gupta ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
In Silico ◽  
Selective Inhibitor ◽  
Monoamine Oxidase B

scholarly journals Coumarin analogue 3-methyl-7H-furo[3,2-g] chromen-7-one as a possible antiparkinsonian agent

Biomédica ◽  
2019 ◽  
Vol 39 (3) ◽  
pp. 491-501
Author(s):  
María del Pilar Olaya ◽  
Nadezdha Esperanza Vergel ◽  
José Luis López ◽  
María Dolores Viña ◽  
Mario Francisco Guerrero
Keyword(s):  
Antioxidant Activity ◽  
Monoamine Oxidase ◽  
Mouse Models ◽  
Inhibitory Activity ◽  
Ex Vivo ◽  
Monoamine Oxidase B ◽  
Mao B ◽  
Continue Research ◽  
Substituted Coumarins

Introduction: Parkinson’s disease is the second most common neurodegenerative disease. Monoamine oxidase B inhibitors are used in the treatment of this disease concomitantly with levodopa or as monotherapy. Several substituted coumarins have shown activity as inhibitors of monoamine oxidase B.Objective: To evaluate the possible antiparkinsonian effects of the coumarin analogue FCS005 (3-methyl-7H-furo[3,2-g]chromen-7-one) in mouse models, as well as its inhibitory activity towards monoamine oxidases (MAO) and its antioxidant activity.Materials and methods: FCS005 was synthesized and the reversal of hypokinesia was evaluated in the reserpine and levodopa models. Moreover, in the haloperidol model, its anticataleptic effects were evaluated. Additionally, the monoamine oxidase inhibitory activity and antioxidant activity of FCS005 were evaluated using in vitro and ex vivo studies, respectively.Results: FCS005 (100 mg/kg) caused the reversal of hypokinesia in the reserpine and levodopa models. This furocoumarin also presented anti-cataleptic effects at the same dose. Besides, it showed selective inhibitory activity towards the MAO-B isoform and antioxidant activity.Conclusion: These results attribute interesting properties to the compound FCS005. It is important to continue research on this molecule considering that it could be a potential antiparkinsonian agent.

scholarly journals Neuroprotective Effect and Mechanism of Thiazolidinedione on Dopaminergic Neurons In Vivo and In Vitro in Parkinson’s Disease

PPAR Research ◽  
2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Yanqin Wang ◽  
Weilin Zhao ◽  
Ge Li ◽  
Jinhu Chen ◽  
Xin Guan ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Neuroprotective Effect ◽  
Oral Treatment ◽  
Treated Group ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nuclear Respiratory Factor

The aim of the present study was to gain insight into the neuroprotection effects and mechanism of thiazolidinedione pioglitazone in both in vitro and in vivo MPP+/MPTP induced PD models. In vivo experimental results showed that oral treatment of pioglitazone resulted in significant improvements in behavior symptoms damaged by MPTP and increase in the survival of TH positive neurons in the pioglitazone intervention groups. In addition, oral treatment of pioglitazone increased the expression of peroxisome proliferator-activated receptor-γ coactivator of 1α (PGC-1α) and increased the number of mitochondria, along with an observed improvement in mitochondrial ultrastructure. From in vitro studies, 2,4-thiazolidinedione resulted in increased levels of molecules regulated function of mitochondria, including PGC-1α, nuclear respiratory factor 1 (NRF1), NRF2, and mitochondria fusion 2 (Mfn2), and inhibited mitochondria fission 1 (Fis1). We show that protein levels of Bcl-2 and ERK were reduced in the MPP+-treated group compared with the control group. This effect was observed to be reversed upon treatment with 2,4-thiazolidinedione, as Bcl-2 and ERK expression levels were increased. We also observed that levels of the apoptotic protein Bax showed opposite changes compared to Bcl-2 and ERK levels. The results from this study confirm that pioglitazone/2,4-thiazolidinedione is able to activate PGC-1α and prevent damage of dopaminergic neurons and restore mitochondria ultrastructure through the regulation of mitochondria function.

scholarly journals Boosting Drug Discovery for Parkinson’s: Enhancement of the Delivery of a Monoamine Oxidase-B Inhibitor by Brain-Targeted PEGylated Polycaprolactone-Based Nanoparticles

Pharmaceutics ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 331 ◽  
Author(s):  
Miguel Pinto ◽  
Carlos Fernandes ◽  
Eva Martins ◽  
Renata Silva ◽  
Sofia Benfeito ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Monoamine Oxidase ◽  
Polymeric Nanoparticles ◽  
Symptomatic Relief ◽  
In Vitro Models ◽  
Monoamine Oxidase B ◽  
Mao B ◽  
Drug Candidates ◽  
Poly Caprolactone

The current pharmacological treatments for Parkinson’s disease only offer symptomatic relief to the patients and are based on the administration of levodopa and catechol-O-methyltransferase or monoamine oxidase-B inhibitors (IMAO-B). Since the majority of drug candidates fail in pre- and clinical trials, due largely to bioavailability pitfalls, the use of polymeric nanoparticles (NPs) as drug delivery systems has been reported as an interesting tool to increase the stealth capacity of drugs or help drug candidates to surpass biological barriers, among other benefits. Thus, a novel potent, selective, and reversible IMAO-B (chromone C27, IC50 = 670 ± 130 pM) was encapsulated in poly(caprolactone) (PCL) NPs by a nanoprecipitation process. The resulting C27-loaded PEGylated PCL NPs (~213 nm) showed high stability and no cytotoxic effects in neuronal (SH-SY5Y), epithelial (Caco-2), and endothelial (hCMEC/D3) cells. An accumulation of PEGylated PCL NPs in the cytoplasm of SH-SY5Y and hCMEC/D3 cells was also observed, and their permeation across Caco-2 and hCMEC/D3 cell monolayers, used as in vitro models of the human intestine and blood-brain barrier, respectively, was demonstrated. PEGylated PCL NPs delivered C27 at concentrations higher than the MAO-B IC50 value, which provides evidence of their relevance to solving the drug discovery pitfalls.

scholarly journals PPAR-, Microglial Cells, and Ocular Inflammation: New Venues for Potential Therapeutic Approaches

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-12 ◽  
Author(s):  
Fiorella Malchiodi-Albedi ◽  
Andrea Matteucci ◽  
Antonietta Bernardo ◽  
Luisa Minghetti
Keyword(s):  
Ocular Inflammation ◽  
Age Related Macular Degeneration ◽  
Microglial Cells ◽  
Brain Diseases ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Age Related ◽  
Ppar Agonists

The last decade has witnessed an increasing interest for the role played by the peroxisome proliferator-activated receptor- (PPAR-) in controlling inflammation in peripheral organs as well as in the brain. Activation of PPAR- has been shown to control the response of microglial cells, the main macrophage population found in brain parenchyma, and limit the inflammation. The anti-inflammatory capacity of PPAR- agonists has led to the hypothesis that PPAR- might be targeted to modulate degenerative brain diseases in which inflammation has been increasingly recognized as a significant component. Recent experimental evidence suggests that PPAR- agonists could be exploited to treat ocular diseases such as diabetic retinopathy, age-related macular degeneration, autoimmune uveitis, and optic neuritis where inflammation has relevant role. Additional PPAR- agonist beneficial effects could involve amelioration of retinal microcirculation and inhibition of neovascularization. However, PPAR- activation could, in some instances, aggravate the ocular pathology, for example, by increasing the synthesis of vascular endothelial growth factor, a proangiogenic factor that could trigger a vicious circle and further deteriorate retinal perfusion. The development of new in vivo and in vitro models to study ocular inflammation and how to modulate for the eye benefit will be instrumental for the search of effective therapies.

scholarly journals Chasing ChEs-MAO B Multi-Targeting 4-Aminomethyl-7-Benzyloxy-2H-Chromen-2-ones

Molecules ◽  
2019 ◽  
Vol 24 (24) ◽  
pp. 4507 ◽  
Author(s):  
Mariagrazia Rullo ◽  
Marco Catto ◽  
Antonio Carrieri ◽  
Modesto de Candia ◽  
Cosimo Damiano Altomare ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Single Point ◽  
Monoamine Oxidase B ◽  
In Vitro Screening ◽  
Binding Modes ◽  
Kinetics Analysis ◽  
Docking Simulations ◽  
Mao B ◽  
Insight Into

A series of 4-aminomethyl-7-benzyloxy-2H-chromen-2-ones was investigated with the aim of identifying multiple inhibitors of cholinesterases (acetyl- and butyryl-, AChE and BChE) and monoamine oxidase B (MAO B) as potential anti-Alzheimer molecules. Starting from a previously reported potent MAO B inhibitor (3), we studied single-point modifications at the benzyloxy or at the basic moiety. The in vitro screening highlighted triple-acting compounds (6, 8, 9, 16, 20) showing nanomolar and selective MAO B inhibition along with IC50 against ChEs at the low micromolar level. Enzyme kinetics analysis toward AChE and docking simulations on the target enzymes were run in order to get insight into the mechanism of action and plausible binding modes.

Molecular Docking Guided Screening of Phytoconstituents from Artemisia iwayomogi as Potential PPARδ Agonists

2019 ◽  
Vol 10 (04) ◽  
pp. 588-596
Author(s):  
Ajmer Singh Grewal ◽  
Neelam Sharma ◽  
Sukhbir Singh
Keyword(s):  
Metabolic Syndrome ◽  
Binding Site ◽  
In Silico ◽  
Binding Free Energy ◽  
Ethanol Extract ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Artemisia Iwayomogi

Metabolic syndrome is a disease condition characterized by decreased insulin sensitivity, hyperlipidemia, abdominal obesity, hypertension, and myocardial diseases, primarily related to a high-fat diet and lack of physical exercise. Peroxisome proliferator-activated receptor (PPAR) δ stimulation changes the body’s energy fuel preference to fats from sugar. PPARδ is expressed universally in all tissues of the human body, particularly those involving lipid metabolism. PPARδ is an evolving pharmacological target for the pharmacotherapeutics of diseases linked to metabolic syndrome. Artemisia iwayomogi ethanol extract was reported as PPARδ agonist and reduced diet-induced overweight via stimulation of fatty acid oxidation in the skeletal muscles. The present study is designed to evaluate in silico some phytoconstituents, including 4 coumarins, 12 flavonoids, 5 phenolic compounds and 7 caffeoyl-quinic acid derivatives found in A. iwayomogi to explore their binding mode and interactions with the PPARδ protein. A total of 28 compounds evaluated in silico, 16 compounds displayed good binding free energy, and significant docking interactions with the binding site residues of PPARδ protein supporting the in vitro PPARδ agonistic activity of A. iwayomogi extract. Amongst these, scopolin, patuletin, patuletin-3-glucoside, 1,2-bis(4-hydroxy-3-methoxyphenyl)prop-1,3-diol, 3-caffeoylquinic acid, and 1,3-dicaffeoylquinic acid displayed most significant binding interactions with binding site residues of PPARδ. This information can be utilized for developing potent and non-toxic natural PPARδ agonists for the management of disorders related to metabolic syndrome.

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