scholarly journals Computer-Aided Drug Discovery Identifies Alkaloid Inhibitors of Parkinson’s Disease Associated Protein, Prolyl Oligopeptidase

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Apoorva M. Kulkarni ◽  
Shailima Rampogu ◽  
Keun Woo Lee
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Docking ◽  
Level Set ◽  
Neurodegenerative Disorder ◽  
Alpha Synuclein ◽  
Interaction Patterns ◽  
Prolyl Oligopeptidase ◽  
Lipinski’S Rule

Parkinson’s disease is a common neurodegenerative disorder marked by the accumulation of the protein alpha synuclein. Studies have indicated the role of prolyl oligopeptidase (POP), a serine protease, in alpha synuclein accumulation. Therefore, POP emerges as an attractive medicinal target. Traditionally, most of the early medicines have been plant-based owing to their ready availability and negligible side effects. Alkaloids owing to their neurotransmitter modulatory, anti-amyloid, anti-oxidant, and anti-inflammatory activities have shown potential in neurodegenerative disease. In this work, we computationally evaluated alkaloid class of phytochemicals for their therapeutic efficacy against POP. Alkaloids were retrieved from the publically available database, Chemical Entities of Biological Interest (ChEBI), and screened for their drug likeness (Lipinski’s rule of 5) and absorption, distribution, metabolism, and excretion, and toxicity (ADMET) in Discovery Studio by ensuring parameters suitable for a central nervous system disease such as blood-brain barrier (BBB) level set to ≤2, absorption level set to 0 and solubility level permitted set to 2, 3, or 4. Next, molecular docking was performed to learn about the affinity of the filtered alkaloids with the POP. Subsequently, molecular dynamic simulations were conducted to assess the reliability and stability of the alkaloid-protein complex. Our study identified metergoline, pipercallosine, celacinnine, lobeline, cystodytin G, lycoperine A, hookerianamide J, and martefragin A as putative lead compounds against POP. Among these, metergoline, pipercallosine, hookerianamide J, and lobeline showed the most promising results. These compounds demonstrated better or equivalent molecular docking scores in comparison to three POP inhibitors that had reached clinical trials, i.e., Z-321, S-17092, and JTP-4819. MD simulations indicated that these compounds remained intact at the active site while adhering to the binding mode and interaction patterns as that of the reported inhibitors. The research conducted here, therefore, provides evidence for conducting in vitro POP inhibitory studies of these newly identified plant-based POP inhibitors.

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.

scholarly journals Protective effects of saffron and its constituent crocetin to motor symptoms, short life span and rough-eyed phenotypes in the fly models of Parkinson’s disease in vivo

2020 ◽  
Author(s):  
Eiji Inoue ◽  
Takahiro Suzuki ◽  
Yasuharu Shimizu ◽  
Keiichi Sudo ◽  
Haruhisa Kawasaki ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Life Span ◽  
Neurodegenerative Disorder ◽  
Neuronal Cell ◽  
Crocus Sativus ◽  
Motor Symptoms ◽  
Protective Effects

AbstractParkinson’s disease (PD) is a common neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the brain. α-Synuclein is an aggregation-prone neural protein that plays a role in the pathogenesis of PD. In our previous paper, we found that saffron; the stigma of Crocus sativus Linné (Iridaceae), and its constituents (crocin and crocetin) suppressed aggregation of α-synuclein and promoted the dissociation of α-synuclein fibrils in vitro. In this study, we investigated the effect of dietary saffron and its constituent, crocetin, in vivo on a fly PD model overexpressing several mutant α-synuclein in a tissue-specific manner. Saffron and crocetin significantly suppressed the decrease of climbing ability in the Drosophila overexpressing A30P (A30P fly PD model) or G51D (G51D fly PD model) mutated α-synuclein in neurons. Saffron and crocetin extended the life span in the G51D fly PD model. Saffron suppressed the rough-eyed phenotype and the dispersion of the size histogram of the ocular long axis in A30P fly PD model in eye. Saffron had a cytoprotective effect on a human neuronal cell line with α-synuclein fibrils. These data showed that saffron and its constituent crocetin have protective effects on the progression of PD disease in animals in vivo and suggest that saffron and crocetin can be used to treat PD.

scholarly journals Alpha-Synuclein Induced Immune Cells Activation and Associated Therapy in Parkinson’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Ruichen Su ◽  
Tian Zhou
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Immune System ◽  
Immune Cells ◽  
Neurodegenerative Disorder ◽  
Alpha Synuclein ◽  
Autoimmune Response ◽  
T Helper ◽  
Helper Type

Parkinson’s disease (PD) is a neurodegenerative disorder closely related to immunity. An important aspect of the pathogenesis of PD is the interaction between α-synuclein and a series of immune cells. Studies have shown that accumulation of α-synuclein can induce an autoimmune response that accelerates the progression of PD. This study discusses the mechanisms underlying the interaction between α-synuclein and the immune system. During the development of PD, abnormally accumulated α-synuclein becomes an autoimmune antigen that binds to Toll-like receptors (TLRs) that activate microglia, which differentiate into the microglia type 1 (M1) subtype. The microglia activate intracellular inflammatory pathways, induce the release of proinflammatory cytokines, and promote the differentiation of cluster of differentiation 4 + (CD4 +) T cells into proinflammatory T helper type 1 (Th1) and T helper type 17 (Th17) subtypes. Given the important role of α-synuclein in the immune system of the patients with PD, identifying potential targets of immunotherapy related to α-synuclein is critical for slowing disease progression. An enhanced understanding of immune-associated mechanisms in PD can guide the development of associated therapeutic strategies in the future.

scholarly journals Peptide TFP5/TP5 derived from Cdk5 activator P35 provides neuroprotection in the MPTP model of Parkinson’s disease

2015 ◽  
Vol 26 (24) ◽  
pp. 4478-4491 ◽  
Author(s):  
BK. Binukumar ◽  
Varsha Shukla ◽  
Niranjana D. Amin ◽  
Philip Grant ◽  
M. Bhaskar ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Neuroprotective Effect ◽  
Selective Inhibition ◽  
Motor Dysfunction ◽  
Dopamine Neurons ◽  
Dopamine Depletion ◽  
Neuroprotective Effects

Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. Recent evidence indicates that cyclin-dependent kinase 5 (Cdk5) is inappropriately activated in several neurodegenerative conditions, including PD. To date, strategies to specifically inhibit Cdk5 hyperactivity have not been successful without affecting normal Cdk5 activity. Previously we reported that TFP5 peptide has neuroprotective effects in animal models of Alzheimer’s disease. Here we show that TFP5/TP5 selective inhibition of Cdk5/p25 hyperactivation in vivo and in vitro rescues nigrostriatal dopaminergic neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP/MPP+) in a mouse model of PD. TP5 peptide treatment also blocked dopamine depletion in the striatum and improved gait dysfunction after MPTP administration. The neuroprotective effect of TFP5/TP5 peptide is also associated with marked reduction in neuroinflammation and apoptosis. Here we show selective inhibition of Cdk5/p25 ­hyperactivation by TFP5/TP5 peptide, which identifies the kinase as a potential therapeutic target to reduce neurodegeneration in Parkinson’s disease.

scholarly journals A Possible Novel Anti-Inflammatory Mechanism for the Pharmacological Prolyl Hydroxylase Inhibitor 3,4-Dihydroxybenzoate: Implications for Use as a Therapeutic for Parkinson’s Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Shankar J. Chinta ◽  
Subramanian Rajagopalan ◽  
Abirami Ganesan ◽  
Julie K. Andersen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Microglial Activation ◽  
Nitrosative Stress ◽  
Neurodegenerative Disorder ◽  
Oxidative And Nitrosative Stress ◽  
Prolyl Hydroxylases ◽  
Age Related

Parkinson’s disease (PD) is an age-related neurodegenerative disorder characterized in part by the preferential loss of nigrostriatal dopaminergic neurons. Although the precise etiology of PD is unknown, accumulating evidence suggests that PD involves microglial activation that exerts neurotoxic effects through production of proinflammatory cytokines and increased oxidative and nitrosative stress. Thus, controlling microglial activation has been suggested as a therapeutic target for combating PD. Previously we demonstrated that pharmacological inhibition of a class of enzymes known as prolyl hydroxylases via 3,4-dihydroxybenzoate administration protected against MPTP-induced neurotoxicity, however the exact mechanisms involved were not elucidated. Here we show that this may be due to DHB’s ability to inhibit microglial activation. DHB significantly attenuated LPS-mediated induction of nitric oxide synthase and pro-inflammatory cytokines in murine BV2 microglial cellsin vitroin conjunction with reduced ROS production and activation of NFκB and MAPK pathways possibly due to up-regulation of HO-1 levels. HO-1 inhibition partially abrogates LPS-mediated NFκB activity and subsequent NO induction.In vivo, DHB pre-treatment suppresses microglial activation elicited by MPTP treatment. Our results suggest that DHB’s neuroprotective properties could be due to its ability to dampen induction of microglial activation via induction of HO-1.

scholarly journals AN IN SILICO STUDY OF NARINGENIN-MEDIATED NEUROPROTECTION IN PARKINSON’S DISEASE

2017 ◽  
Vol 10 (8) ◽  
pp. 171
Author(s):  
Saurabh Kumar Jha ◽  
Pravir Kumar
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Docking ◽  
In Silico ◽  
E3 Ligase ◽  
Docking Studies ◽  
Dimensional Structure ◽  
Molecular Docking Studies ◽  
Lipinski’S Rule ◽  
Ubiquitin E3 Ligase

  Objective: Naringenin is a dietary biomolecule with broad spectrum of activities which protects neurons from various neurotoxic insults and improves cognition and motor function in neurodegenerative diseases. DJ-1 has both, ubiquitin E3 ligase as well as chaperonic activity, and loss of ubiquitin E3 ligase activity of DJ-1 has been found to be associated with familial Parkinson’s disease (PD). Naringenin induced E3 ligase activity of DJ-1 which can have possible clinical relevance in PD.Methods: Various in silico parameters such as phylogenetic analysis, homology modeling, active site prediction, and molecular docking studies using AutoDock 4.2.1 and LIGPLOT1.4.5 were carried out.Results: Three-dimensional structure of DJ-1 was generated and Ramachandran plot was obtained for quality assessment. RAMPAGE displayed 99.5% of residues in the most favored regions. 0% residues in additionally allowed and 0.5% disallowed regions of DJ-1 protein. Further, initial screenings of the molecules were done based on Lipinski’s rule of five. CastP server used to predict the ligand binding site suggests that this protein can be utilized as a potential drug target. Finally, we have found naringenin to be most effective among four biomolecules in modulating DJ-1 based on minimum inhibition constant, Ki, and highest negative free energy of binding with maximum interacting surface area in the course of docking studies.Conclusion: Our study suggests that based on different in silico parameters and molecular docking studies, naringenin can provide a new avenue for PD therapeutics.

A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson’s disease

2020 ◽  
Vol 12 (560) ◽  
pp. eaau3960
Author(s):  
Ibrahim Boussaad ◽  
Carolin D. Obermaier ◽  
Zoé Hanss ◽  
Dheeraj R. Bobbili ◽  
Silvia Bolognin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disorder ◽  
Neuronal Cell ◽  
Exon Skipping ◽  
Cell Loss ◽  
Genetically Engineered ◽  
Neuronal Precursor Cells

Parkinson’s disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic forms of the disease. Using a patient-based in vitro model of PARK7-linked PD, we identified a U1-dependent splicing defect causing a drastic reduction in DJ-1 protein and, consequently, mitochondrial dysfunction. Targeting defective exon skipping with genetically engineered U1-snRNA recovered DJ-1 protein expression in neuronal precursor cells and differentiated neurons. After prioritization of candidate drugs, we identified and validated a combinatorial treatment with the small-molecule compounds rectifier of aberrant splicing (RECTAS) and phenylbutyric acid, which restored DJ-1 protein and mitochondrial dysfunction in patient-derived fibroblasts as well as dopaminergic neuronal cell loss in mutant midbrain organoids. Our analysis of a large number of exomes revealed that U1 splice-site mutations were enriched in sporadic PD patients. Therefore, our study suggests an alternative strategy to restore cellular abnormalities in in vitro models of PD and provides a proof of concept for neuroprotection based on precision medicine strategies in PD.

P1-303 Alpha-synuclein protein implicated in Parkinson's disease binds copper in vitro

2004 ◽  
Vol 25 ◽  
pp. S182
Author(s):  
Jenny E. King ◽  
Fiona E. Benson ◽  
Hao Zhang ◽  
David Allsop
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Alpha Synuclein

scholarly journals Neuroregeneration in Parkinson’s Disease: From Proteins to Small Molecules

2019 ◽  
Vol 17 (3) ◽  
pp. 268-287 ◽  
Author(s):  
Yulia A. Sidorova ◽  
Konstantin P. Volcho ◽  
Nariman F. Salakhutdinov
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Small Molecules ◽  
Neurodegenerative Disorder ◽  
Dopamine Neurons ◽  
Current Therapy ◽  
Small Molecular Weight ◽  
Diagnostic Symptoms ◽  
Nigrostriatal Dopamine Neurons

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, the lifetime risk of developing this disease is 1.5%. Motor diagnostic symptoms of PD are caused by degeneration of nigrostriatal dopamine neurons. There is no cure for PD and current therapy is limited to supportive care that partially alleviates disease signs and symptoms. As diagnostic symptoms of PD result from progressive degeneration of dopamine neurons, drugs restoring these neurons may significantly improve treatment of PD. </P><P> Method: A literature search was performed using the PubMed, Web of Science and Scopus databases to discuss the progress achieved in the development of neuroregenerative agents for PD. Papers published before early 2018 were taken into account. </P><P> Results: Here, we review several groups of potential agents capable of protecting and restoring dopamine neurons in cultures or animal models of PD including neurotrophic factors and small molecular weight compounds. </P><P> Conclusion: Despite the promising results of in vitro and in vivo experiments, none of the found agents have yet shown conclusive neurorestorative properties in PD patients. Meanwhile, a few promising biologicals and small molecules have been identified. Their further clinical development can eventually give rise to disease-modifying drugs for PD. Thus, intensive research in the field is justified.

scholarly journals The Neuro-Protective Effects of the TSPO Ligands CB86 and CB204 on 6-OHDA-Induced PC12 Cell Death as an In Vitro Model for Parkinson’s Disease

Biology ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1183
Author(s):  
Sheelu Monga ◽  
Nunzio Denora ◽  
Valentino Laquintana ◽  
Rami Yashaev ◽  
Abraham Weizman ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Neurodegenerative Disorder ◽  
Reactive Oxygen ◽  
Ros Generation ◽  
Oxygen Species ◽  
The Impact

Parkinson’s disease (PD) is a progressive neurodegenerative disorder which is characterized by the degeneration of dopaminergic neurons in substantia nigra (SN). Oxidative stress or reactive oxygen species (ROS) generation was suggested to play a role in this specific type of neurodegeneration. Therapeutic options which can target and counteract ROS generation may be of benefit. TSPO ligands are known to counteract with neuro-inflammation, ROS generation, apoptosis, and necrosis. In the current study, we investigated an in vitro cellular PD model by the assessment of 6-hydroxydopamine (6-OHDA, 80 µM)-induced PC12 neurotoxicity. Simultaneously to the exposure of the cells to 6-OHDA, we added the TSPO ligands CB86 and CB204 (25 µM each) and assessed the impact on several markers of cell death. The two ligands normalized significantly (57% and 52% respectively, from 44%; whereas the control was 68%) cell proliferation at different time points from 0–24 h. Additionally, we evaluated the effect of these two TSPO ligands on necrosis using propidium iodide (PI) staining and found that the ligands inhibited significantly the 6-OHDA-induced necrosis. As compared to control, the red count was increased up to 57-fold whereas CB86 and CB204 inhibited to 2.7-fold and 3.2-fold respectively. Necrosis was also analyzed by LDH assay which showed significant effect. Both assays demonstrated similar potent anti-necrotic effect of the two TSPO ligands. Reactive oxygen species (ROS) generation induced by 6-OHDA was also inhibited by the two TSPO ligand up to 1.3 and 1.5-fold respectively, as compared to 6-OHDA group. CB86 and CB204 inhibited also normalized the cell viability up to 1.8-fold after the exposure to 6-OHDA, as assessed by XTT assay. The two TSPO ligands also inhibited apoptosis significantly (1.3-fold for both) as assessed by apopxin green staining. In summary, it appears that the two TSPO ligands CB86 and CB204 can suppress cell death of PC12 induced by 6-OHDA. The results may be relevant to the use of these two TSPO ligands as therapeutic option neurodegenerative diseases like PD.

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