In silico identification of potent inhibitors of alpha-synuclein aggregation and its in vivo evaluation using MPTP induced Parkinson mice model

By activating PPAR-γ, thiazolidinediones normalize glucose levels in animal models of type 2 diabetes and in patients with this pathology. The aim of the present study was to analyze 219 new derivatives in silico and select the best for synthesis, to be evaluated for acute oral toxicity in female rats and for control of diabetes-related parameters in a rat model of streptozotocin-induced diabetes. The best compound was chosen based on pharmacokinetic, pharmacodynamic, and toxicological parameters obtained in silico and binding orientation observed by docking simulations on PPAR-γ. Compound 1G was synthesized by a quick and easy Knoevenagel condensation. Acute oral toxicity was found at a dose greater than 2000 mg/Kg. Compound 1G apparently produces therapeutic effects similar to those of pioglitazone, decreasing glycaemia and triglyceride levels in diabetic animals, without liver damage. Moreover, it did not cause a significant weight gain and tended to reduce polydipsia and polyphagia, while diminishing systemic inflammation related to TNF-α and IL-6. It lowered the level of endogenous antioxidant molecules such as reduced glutathione and glutathione reductase. In conclusion, 1G may be a candidate for further testing as an euglycemic agent capable of preventing the complications of diabetes.

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Synthesis and characterization of Chitosan-Catechol conjugates: Development and in vitro, in silico and in vivo evaluation of mucoadhesive pellets of lafutidine

Journal of Bioactive and Compatible Polymers ◽

10.1177/0883911521997849 ◽

2021 ◽

pp. 088391152199784

Author(s):

Loveleen Kaur ◽

Ajay Kumar Thakur ◽

Pradeep Kumar ◽

Inderbir Singh

Keyword(s):

Drug Release ◽

In Silico ◽

Ex Vivo ◽

Strong Interactions ◽

Dissolution Time ◽

Sem Images ◽

In Vivo Evaluation ◽

Release Studies

Present study was aimed to synthesize and characterize Chitosan-Catechol conjugates and to design and develop mucoadhesive pellets loaded with lafutidine. SEM images indicated the presence of fibrous structures responsible for enhanced mucoadhesive potential of Chitosan-Catechol conjugates. Thermodynamic stability and amorphous nature of conjugates was confirmed by DSC and XRD studies respectively. Rheological studies were used to evaluate polymer mucin interactions wherein strong interactions between Chitosan-Catechol conjugate and mucin was observed in comparison to pristine chitosan and mucin. The mucoadhesion potential of Chitosan-Catechol (Cht-C) versus Chitosan (Cht) was assessed in silico using molecular mechanics simulations and the results obtained were compared with the in vitro and ex vivo results. Cht-C/mucin demonstrated much higher energy stabilization (∆E ≈ −65 kcal/mol) as compared to Cht/mucin molecular complex. Lafutidine-loaded pellets were prepared from Chitosan (LPC) and Chitosan-Catechol conjugates (LPCC) and were evaluated for various physical properties viz. flow, circularity, roundness, friability, drug content, particle size and percent mucoadhesion. In vitro drug release studies on LPC and LPCC pellets were performed for computing t50%, t90% and mean dissolution time. The values of release exponent from Korsmeyer-Peppas model was reported to be 0.443 and 0.759 for LPC and LPCC pellets suggesting Fickian and non-Fickian mechanism representing drug release, respectively. In vivo results depicted significant controlled release and enhanced residence of the drug after being released from the chitosan-catechol coated pellets. Chitosan-Catechol conjugates were found to be a promising biooadhesive polymer for the development of various mucoadhesive formulations.

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In silico identification of viper phospholipaseA2 inhibitors: validation by in vitro, in vivo studies

Journal of Molecular Modeling ◽

10.1007/s00894-011-0994-7 ◽

2011 ◽

Vol 17 (12) ◽

pp. 3063-3073 ◽

Cited By ~ 9

Author(s):

Amit Nargotra ◽

Sujata Sharma ◽

Mohd Iqbal Alam ◽

Zabeer Ahmed ◽

Asha Bhagat ◽

...

Keyword(s):

In Silico ◽

In Vivo Studies ◽

In Silico Identification

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N-pyridin-2-yl benzamide analogues as allosteric activators of glucokinase: Design, synthesis, in vitro,in silico and in vivo evaluation

Chemical Biology & Drug Design ◽

10.1111/cbdd.13423 ◽

2018 ◽

Vol 93 (3) ◽

pp. 364-372 ◽

Cited By ~ 2

Author(s):

Ajmer Singh Grewal ◽

Rajeev Kharb ◽

Deo Nandan Prasad ◽

Jagdeep Singh Dua ◽

Viney Lather

Keyword(s):

In Silico ◽

In Vivo Evaluation ◽

Design Synthesis

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Neuroprotective and Neurorescue Mode of Action of Bacopa monnieri (L.) Wettst in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Parkinson’s Disease: An In Silico and In Vivo Study

Frontiers in Pharmacology ◽

10.3389/fphar.2021.616413 ◽

2021 ◽

Vol 12 ◽

Author(s):

Babita Singh ◽

Shivani Pandey ◽

Mohammad Rumman ◽

Shashank Kumar ◽

Prem Prakash Kushwaha ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

In Silico ◽

Dopaminergic Neurons ◽

Lipid Peroxide ◽

Bacopa Monnieri ◽

Dopamine Level ◽

Mice Model ◽

Mptp Administration

Ethnopharmacological Relevance: Parkinson’s disease (PD) is characterized by progressive death of dopaminergic neurons. The presently used medicines only tackle the symptoms of PD, but none makes a dent on the processes that underpin the disease’s development. Herbal medicines have attracted considerable attention in recent years. Bacopa monnieri (L.) Wettst (Brahmi) has been used in Indian Ayurvedic medicine to enhance memory and intelligence. Herein, we assessed the neuroprotective role of Bacopa monnieri (L.) Wettst on Parkinson’s disease.Aim of the Study:Bacopa monnieri (L.) Wettst, a medicinal herb, is widely used as a brain tonic. We investigated the neuroprotective and neurorescue properties of Bacopa monnieri (L.) Wettst extract (BME) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model of PD.Materials and Methods: The mice model of MPTP-induced PD is used in the study. In the neuroprotective (BME + MPTP) and neurorescue (MPTP + BME) experiments, the animals were administered 40 mg/kg body weight BME orally before and after MPTP administration, respectively. Effect of BME treatment was evaluated by accessing neurobehavioral parameters and levels of dopamine, glutathione, lipid peroxide, and nitrites. An in silico study was performed using AutoDock Tools 1.5.6 (ADT).Results: A significant recovery in behavioral parameters, dopamine level, glutathione level, lipid peroxides, and nitrite level was observed in BME-treated mice. Treatment with BME before or after MPTP administration has a protective effect on dopaminergic neurons, as evidenced by a significant decrease in GFAP immunostaining and expression of inducible nitric oxide synthase (iNOS) in the substantia nigra region; however, the degree of improvement was more prominent in mice receiving BME treatment before MPTP administration. Moreover, the in silico study revealed that the constituents of BM, including bacosides, bacopasides, and bacosaponins, can inactivate the enzyme monoamine oxidase B, thus preventing the breakdown of MPTP to MPP+.Conclusion: Our results showed that BME exerts both neuroprotective and neurorescue effects against MPTP-induced degeneration of the nigrostriatal dopaminergic neurons. Moreover, BME may slow down the disease progression and delay the onset of neurodegeneration in PD.

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In silico identification and in vivo validation of a set of evolutionary conserved plant root-specific cis-regulatory elements

Mechanisms of Development ◽

10.1016/j.mod.2012.03.002 ◽

2013 ◽

Vol 130 (1) ◽

pp. 70-81 ◽

Cited By ~ 3

Author(s):

Aurélie Christ ◽

Ira Maegele ◽

Nati Ha ◽

Hong Ha Nguyen ◽

Martin D. Crespi ◽

...

Keyword(s):

In Silico ◽

Plant Root ◽

Regulatory Elements ◽

In Silico Identification ◽

In Vivo Validation

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In vitro and in vivo Evaluation of in silico Predicted Pneumococcal UDPG:PP Inhibitors

Frontiers in Microbiology ◽

10.3389/fmicb.2020.01596 ◽

2020 ◽

Vol 11 ◽

Cited By ~ 1

Author(s):

Freya Cools ◽

Dhoha Triki ◽

Nele Geerts ◽

Peter Delputte ◽

Denis Fourches ◽

...

Keyword(s):

In Silico ◽

In Vivo Evaluation

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[18F]Amylovis as a Potential PET Probe for β-Amyloid Plaque: Synthesis, In Silico, In vitro and In vivo Evaluations

Current Radiopharmaceuticals ◽

10.2174/1874471012666190102165053 ◽

2019 ◽

Vol 12 (1) ◽

pp. 58-71 ◽

Cited By ~ 2

Author(s):

Suchitil Rivera-Marrero ◽

Laura Fernández-Maza ◽

Samila León-Chaviano ◽

Marquiza Sablón-Carrazana ◽

Alberto Bencomo-Martínez ◽

...

Keyword(s):

In Silico ◽

Specific Activity ◽

Senile Plaques ◽

Coupling Reaction ◽

In Vitro Assays ◽

Mice Model ◽

Wild Mice ◽

In Silico Studies

Background: Alzheimer’s disease (AD) is the most common form of dementia. Neuroimaging methods have widened the horizons for AD diagnosis and therapy. The goals of this work are the synthesis of 2-(3-fluoropropyl)-6-methoxynaphthalene (5) and its [18F]-radiolabeled counterpart ([18F]Amylovis), the in silico and in vitro comparative evaluations of [18F]Amylovis and [11C]Pittsburg compound B (PIB) and the in vivo preclinical evaluation of [18F]Amylovis in transgenic and wild mice. Methods: Iron-catalysis cross coupling reaction, followed by fluorination and radiofluorination steps were carried out to obtain 5 and 18F-Amylovis. Protein/Aß plaques binding, biodistribution, PET/CT Imaging and immunohistochemical studies were conducted in healthy/transgenic mice. Results: The synthesis of 5 was successful obtained. Comparative in silico studies predicting that 5 should have affinity to the Aβ-peptide, mainly through π-π interactions. According to a dynamic simulation study the ligand-Aβ peptide complexes are stable in simulation-time (ΔG = -5.31 kcal/mol). [18F]Amylovis was obtained with satisfactory yield, high radiochemical purity and specific activity. The [18F]Amylovis log Poct/PBS value suggests its potential ability for crossing the blood brain barrier (BBB). According to in vitro assays, [18F]Amylovis has an adequate stability in time. Higher affinity to Aβ plaques were found for [18F]Amylovis (Kd 0.16 nmol/L) than PIB (Kd 8.86 nmol/L) in brain serial sections of 3xTg-AD mice. Biodistribution in healthy mice showed that [18F]Amylovis crosses the BBB with rapid uptake (7 %ID/g at 5 min) and good washout (0.11±0.03 %ID/g at 60 min). Comparative PET dynamic studies of [18F]Amylovis in healthy and transgenic APPSwe/PS1dE9 mice, revealed a significant high uptake in the mice model. Conclusion: The in silico, in vitro and in vivo results justify that [18F]Amylovis should be studied as a promissory PET imaging agent to detect the presence of Aβ senile plaques.

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