Open Access Articles | An Integrated Computational Approach for Plant-Based Protein Tyrosine Phosphatase Non-Receptor Type 1 Inhibitors

 

Journal Name: Current Computer-Aided Drug Design

Author(s): Shabana Bibi, Katsumi Sakata*.

 

 

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Abstract:

Background: Protein tyrosine phosphatase non-receptor type 1 is a therapeutic target for the type 2 diabetes mellitus. According to the International Diabetes Federation 2015 report, one out of 11 adults suffers from diabetes mellitus globally.

Objective: Current anti-diabetic drugs can cause life-threatening side-effects. The present study proposes a pipeline for the development of effective and plant-derived anti-diabetic drugs that may be safer and better tolerated.

Methods: Plant-derived protein tyrosine phosphatase non-receptor type 1 inhibitors possessing antidiabetic activity less than 10µM were used as a training set. A common feature pharmacophore model was generated. Pharmacophore-based screening of plant-derived compounds of the ZINC database was conducted using ZINCpharmer. Screened hits were assessed to evaluate their drug-likeness, pharmacokinetics, detailed binding behavior, and aggregator possibility based on their physiochemical properties and chemical similarity with reported aggregators.

Results: Through virtual screening and in silico pharmacology protocol isosilybin (ZINC30731533) was identified as a lead compound with optimal properties. This compound can be recommended for laboratory tests and further analyses to confirm its activity as protein tyrosine phosphatase nonreceptor type 1 inhibitor.

Conclusion: The present study has identified plant-derived anti-diabetic virtual lead compound with the potential to inhibit protein tyrosine phosphatase non-receptor type 1, which may be helpful to enhance insulin production. This computer-aided study could facilitate the development of novel pharmacological inhibitors for diabetes treatment. To read out more, please visit: http://www.eurekaselect.com/151386/article

New Issue | Current Drug Metabolism (Volume: 20, Issue: 5)

 

Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism, pharmacokinetics, and drug disposition. The journal serves as an international forum for the publication of full-length/mini review, research articles and guest edited issues in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the most important developments. The journal covers the following general topic areas: pharmaceutics, pharmacokinetics, toxicology, and most importantly drug metabolism.

More specifically, in vitro and in vivo drug metabolism of phase I and phase II enzymes or metabolic pathways; drug-drug interactions and enzyme kinetics; pharmacokinetics, pharmacokinetic-pharmacodynamic modeling, and toxicokinetics; interspecies differences in metabolism or pharmacokinetics, species scaling and extrapolations; drug transporters; target organ toxicity and interindividual variability in drug exposure-response; extrahepatic metabolism; bioactivation, reactive metabolites, and developments for the identification of drug metabolites. Preclinical and clinical reviews describing the drug metabolism and pharmacokinetics of marketed drugs or drug classes.

 

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Articles from the journal: Current Drug Metabolism; Volume: 20, Issue: 5

 

For details on the articles, please visit this link: http://www.eurekaselect.com/node/592/current-drug-metabolism/issue/20/2559/5/9141

Editor’s Choice Article | Unequal Absorption of Radiolabeled and Nonradiolabeled Drug from the Oral Dose Leads to Incorrect Estimates of Drug Absorption and Circulating Metabolites in a Mass Balance Study

Journal Name: Drug Metabolism Letters

Author(s): Ryan H. Takahashi*, Jae H. Chang, Jodie Pang, Xiaorong Liang, Shuguang Ma.

 

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Mass balance studies conducted using radiolabeled material (14C or 3H) definitively characterize the Absorption, Metabolism, and Excretion (AME) of a drug. A critical aspect of these studies is that the radiotracer maintains its proportion to total drug from its administration to its complete elimination from the body. In the study of GDC-0276 in beagle dogs, we observed that the 14C radiotracer proportion (specific activity) varied through the study.

High resolution-accurate mass spectrometric measurements of 12C and 14C isotopes of GDC- 0276 and its metabolites in plasma and excreta samples were used to determine the apparent specific activities, which were higher than the specific activity of the dosing formulation. Drug concentrations were adjusted to the observed specific activities to correct the readouts for GDC-0276 AME and PK. Read out full article at:  http://www.eurekaselect.com/167902/article

 

MOST ACCESSED ARTICLE – Opioids in the Frame of New Psychoactive Substances Network: A Complex Pharmacological and Toxicological Issue

Journal Name: Current Molecular Pharmacology

Author(s): Ludovic Ventura, Felix Carvalho, Ricardo Jorge Dinis-Oliveira*.

 

 

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Abstract:

Background: New psychoactive substances (NPS), often referred to as “legal highs” or “designer drugs”, are derivatives and analogues of existing psychoactive drugs that are introduced in the recreational market to circumvent existing legislation on drugs of abuse.

Objective: This systematic review aims to gather the state of the art regarding chemical, molecular pharmacology and toxicological information of opioid class of NPS.

Methods: Chemical, pharmacological, toxicological and clinical effects of opioid class of NPS were searched in books and in PubMed (U.S. National Library of Medicine) without a limiting period.

Results: Within this class, fentanyl analogues are among the most frequently abused and pose several clinical concerns and therefore will be thoroughly discussed. Other opioid sub-categories of NPS frequently misused include AH-7921, MT-45, U-47700, U-50488, desomorphine, mitragynine, tramadol, tapentadol, salvinorin A and its analogue herkinorin.

Conclusion: Due to inefficient monitoring techniques, as well as limited knowledge regarding the acute and long-term effects of opioids NPS, further clinical and forensic toxicological studies are required.

 

 

READ MORE HERE: http://www.eurekaselect.com/153703

OPEN ACCESS ARTICLE – Pharmacokinetics, Pharmacodynamics and Pharmacogenetics of Tacrolimus in Kidney Transplantation

Journal Name: Current Drug Metabolism

Author(s): Meng Yu, Mouze Liu, Wei Zhang, Yingzi Ming*.

 

 

 

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Abstract:

Background: Tacrolimus (Tac, or FK506), a calcineurin inhibitor (CNI), is the first-line immunosuppressant which consists of the footstone as immunosuppressive regimens in kidney transplantation. However, the drug toxicity and the significant differences of pharmacokinetics (PK) and pharmacodynamics (PD) among individuals are hidden troubles for clinical application. Recently, emerging evidences of Tac pharmacogenetics (PG) regarding drug absorption, metabolism, disposition, excretion and response are discovered for better understanding of this drug.

Method: We reviewed the published articles regarding the Tac PG and its effects on PK and PD in kidney transplantation. In addition, we summarized information on polygenic algorithms.

Results: The polymorphism of genes encoding metabolic enzymes and transporters related to Tac were largely investigated, but the results were inconsistent. In addition to CYP3A4, CYP3A5 and P-gp (also known as ABCB1), single nucleotide polymorphisms (SNPs) might also affect the PK and PD parameters of Tac.

Conclusion: The correlation between Tac PK, PD and PG is very complex. Although many factors need to be verified, it is envisaged that thorough understanding of PG may assist clinicians to predict the optimal starting dosage, help adjust the maintenance regimen, as well as identify high risk patients for adverse effects or drug inefficacy.

READ MORE HERE: http://www.eurekaselect.com/159463

OPEN ACCESS ARTICLE – Serotonin Receptor Binding Characteristics of Geissoschizine Methyl Ether, an Indole Alkaloid in Uncaria Hook

Journal Name: Current Medicinal Chemistry

Author(s): Yasushi Ikarashi, Kyoji Sekiguchi, Kazushige Mizoguchi*.

 

Abstract:

Background: Geissoschizine methyl ether (GM) is one of the indole alkaloids in Uncaria hook, and an active ingredient of yokukansan (YKS) that improves behavioral and psychological symptoms of dementia (BPSD) in patients with several types of dementia. The pharmacological action of GM has been related to various serotonin (5-HT) receptor subtypes.

Objective: The aim of this article is to review the binding characteristics of GM to the 5-HT receptor subtypes in the brains using our own data and previous findings.

Method: Competitive receptor-binding and agonist/antagonist activity assays for several 5-HT receptor subtypes were performed. Moreover, the articles describing pharmacokinetics and brain distribution of GM were searched in PubMed.

Results: GM bound the following 5-HT receptor subtypes: 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5- HT4, 5-HT5A, 5-HT6, and 5-HT7. Among these receptors, GM had partial agonistic activity for 5-HT1A receptors and antagonistic activity for 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors. Also, GM was metabolized by various CYP isoforms, mainly CYP3A4. Parent/unchanged GM was detected in both the blood and brain of rats after oral administration of YKS. In the brains, GM was presumed to bind to 5- HT1A, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors on neuron-like large cells mainly in the frontal cortex.

Conclusion: These results suggest that GM is a pharmacologically important alkaloid that regulates various serotonergic activities or functions by binding to multiple 5-HT receptor subtypes. Thus, this review provides recent 5-HT receptor-related evidence that GM is partly responsible for pharmacological effects of YKS.

 

READ MORE HERE: http://www.eurekaselect.com/151003 

Highlighted Article – Intravesical Chemotherapy and Chemohyperthermia in Non-Muscle-Invasive Bladder Cancer – Current Drug Metabolism

CDM- Articles_18-12-Gad M. Lev

To access this article, please visit: http://www.eurekaselect.com/151926

Testimonial by Gina Paola Domínguez Moré!

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Contributed Article: “Pharmacokinetics of Botanical Drugs and Plant Extracts

Podcast: Intravesical Chemotherapy And Chemohypherthermia In Non-Muscle-Invasive Bladder Cancer

Author(s):Fabio Campodonico, Savino Di Stasi , Gad M Lev, Carlo Terrone, Luca Bongiovanni, Francesca Mattioli, Vincenzo Pagliarulo, Carlo Introini.Fabio Campodonico, Savino Di Stasi , Gad M Lev, Carlo Terrone, Luca Bongiovanni, Francesca Mattioli, Vincenzo Pagliarulo, Carlo Introini.

For article details, visit: http://www.eurekaselect.com/151926/article

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Upcoming Thematic Issue – Recent Development of Drug Delivery systems for improving Bioavailability and Pharmacokinetics

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http://www.eurekaselect.com/592/journal/current-drug-metabolism

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