High-resolution MD simulation studies to get mechanistic insights into the urea-induced denaturation of human Sphingosine kinase 1

2021 ◽  
Vol 21 ◽  
Author(s):  
Faez Iqbal Khan ◽  
Shahid Ali ◽  
Wenjing Chen ◽  
Farah Anjum ◽  
Alaa Shafie ◽  
...  
Keyword(s):  
Time Scale ◽  
Md Simulation ◽  
Structural Changes ◽  
Sphingosine Kinase ◽  
Md Simulations ◽  
Sphingosine Kinase 1 ◽  
Cellular Survival ◽  
Constant Form ◽  
The Impact ◽  
Unfolding Kinetics

Background: Sphingosine kinase 1 (SPhK1) is a crucial signaling enzyme involved in cell proliferation, cellular survival, stimulation of angiogenesis, and apoptosis prevention. Recently, we have reported the unfolding kinetics of SPhK1 using molecular dynamics (MD) simulation, circular dichroism and fluorescence spectroscopy. We found that SPhK1 showed a biphasic unfolding with an intermediate state (~ 4.0 M urea). Objective: We aim to understand the impact of MD simulation duration on the structure, function and dynamics of proteins. In order to get deeper insights into the folding mechanism an extended MD simulation is required. Method: Here, we extended the MD simulations time scale from 100 to 300 ns on SPhK1 at increasing urea concentration to explore structural changes in the SPhK1. Results: The results suggested a constant form of the unfolding of SPhK1 upon extending the simulation time scale at different urea concentrations. Furthermore, we showed step by step unfolding and percentage of secondary structure contents in SPhK1 under the influence of urea at each concentration. Conclusion: The results from the current work revealed a uniform pattern of the SPhK1 unfolding at different urea concentrations. This study provides deeper mechanistic insights into the urea-induced denaturation of SPhK1.

Discovery of novel sphingosine kinase 1 inhibitorsvia structure-based hierarchical virtual screening

MedChemComm ◽  
2015 ◽  
Vol 6 (3) ◽  
pp. 413-417 ◽  
Author(s):  
Xiaojian Wang ◽  
Chenbin Sun ◽  
Liang Fang ◽  
Dali Yin
Keyword(s):  
Virtual Screening ◽  
Sphingosine Kinase ◽  
Md Simulations ◽  
Binding Pocket ◽  
Binding Mode ◽  
Positive Control ◽  
Biological Evaluation ◽  
U937 Cells ◽  
Sphingosine Kinase 1 ◽  
Inhibitory Activities

Hierarchical structure-based virtual screening against the sphingosine kinase 1(SphK1) binding pocket was performed. 25 compounds were selected for biological evaluation. Compound 25 exhibited comparable SphK1 and SphK2 inhibitory activities and anti-proliferative effects on U937 cells to the positive control N,N-dimethylsphingosine (DMS) 1. Further molecule dynamic (MD) simulations revealed the binding mode between SphK1 and 25.

scholarly journals The Impact of Sphingosine Kinase-1 in Head and Neck Cancer

Biomolecules ◽  
2013 ◽  
Vol 3 (4) ◽  
pp. 481-513 ◽  
Author(s):  
Paulette Tamashiro ◽  
Hideki Furuya ◽  
Yoshiko Shimizu ◽  
Kayoko Iino ◽  
Toshihiko Kawamori
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Neck Cancer ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 1 ◽  
The Impact

DDRE-19. SPHINGOSINE KINASE 1 AS A THERAPEUTIC TARGET FOR IDH1-R132H mut GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi78-vi78
Author(s):  
Tyrone Dowdy ◽  
Tomohiro Yamasaki ◽  
Lumin Zhang ◽  
Orieta Celiku ◽  
Adrian Lita ◽  
...  
Keyword(s):  
Glioma Cells ◽  
Sphingosine Kinase ◽  
Vital Role ◽  
The Cancer Genome Atlas ◽  
Sphingolipid Metabolism ◽  
Sphingosine Kinase 1 ◽  
Western Blots ◽  
Idh1 R132h ◽  
The Impact

Abstract BACKGROUND Our study aimed to identify vulnerabilities within sphingolipid metabolism with potential to translate to therapeutics. While the vital role of sphingolipids in maintaining rheostat balance and as secondary messengers for signaling pathways (involving proliferation, invasion, migration, and angiogenesis) has been well-documented, their role has not been widely investigated in gliomas. Therefore, metabolic analysis of sphingolipid pathway for IDH1-R132H (IDH1 mut ) glioma cell lines was conducted in order to elucidate susceptible targets. METHODS Global sphingolipid quantification utilized high-throughput LCMS analysis. Pathway protein expression was measured via Western blots in vitro and derived from patients using The Cancer Genome Atlas analysis. RESULTS We probed the impact of decreasing D-2HG on the sphingolipid metabolism after treating a panel of IDH1 mut glioma cells with IDH1-R132H mut inhibitor, AGI5198. This revealed significant downregulation of N,N-dimethylsphingosine (NDMS), C17-sphingosine, and C18-sphinganine. Coincidentally, sphingosine-1-phosphate (S1P) was significantly upregulated in these gliomas. We conducted rational drug screen which revealed that inhibition of SPHK1 with N,N-dimethylsphingosine in combination with C17-sphingosine triggered biostatic dose-response across IDH1 mut gliomas and low impact on IDH WT glioblastoma (GBM) cells. Western analysis revealed that the IDH1 mut gliomas and IDH WT GBM expressed sphingosine kinase-1 (SPHK1). Data also unveiled a discovery that SPHK2 was highly expressed in the GBM cells while remarkably absent in the glioma cells. CONCLUSION Herein, we provide evidence that certain IDH1 mut gliomas present epigenetic silencing of SPHK2 which creates dependency on SPHK1 for S1P; thus, increasing sensitivity to targeting sphingolipid metabolism, and creating susceptibility to proliferation arrest and subsequent cellular death. S1P production has been reported to be elevated particularly for malignant glioblastomas in prior studies; whereas our research revealed that it is relatively low in IDH mut by comparison with IDH WT tumor cells. These findings suggest targeting the sphingolipid metabolism may present a promising strategy to improve survival for patients diagnosed with IDH1 mut gliomas.

scholarly journals The Influence of Calcium toward Order/Disorder Conformation of Repeat-in-Toxin (RTX) Structure of Family I.3 Lipase from Pseudomonas fluorescens AMS8

Toxins ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 579
Author(s):  
Nur Shidaa Mohd Ali ◽  
Abu Bakar Salleh ◽  
Thean Chor Leow ◽  
Raja Noor Zaliha Raja Abd Rahman ◽  
Mohd Shukuri Mohamad Ali
Keyword(s):  
Calcium Binding ◽  
Metal Ion ◽  
Md Simulation ◽  
Structural Changes ◽  
Decisive Role ◽  
Md Simulations ◽  
High Binding Energy ◽  
Docking Analysis ◽  
Repeat Structure ◽  
Functional Dynamics

Calcium-binding plays a decisive role in the folding and stabilization of many RTX proteins, especially for the RTX domain. Although many studies have been conducted to prove the contribution of Ca2+ ion toward the folding and stabilization of RTX proteins, its functional dynamics and conformational structural changes remain elusive. Here, molecular docking and molecular dynamics (MD) simulations were performed to analyze the contribution of Ca2+ ion toward the folding and stabilization of the RTX lipase (AMS8 lipase) structure. AMS8 lipase contains six Ca2+ ions (Ca1–Ca6). Three Ca2+ ions (Ca3, Ca4, and Ca5) were bound to the RTX parallel β-roll motif repeat structure (RTX domain). The metal ion (Ca2+) docking analysis gives a high binding energy, especially for Ca4 and Ca5 which are tightly bound to the RTX domain. The function of each Ca2+ ion is further analyzed using the MD simulation. The removal of Ca3, Ca4, and Ca5 caused the AMS8 lipase structure to become unstable and unfolded. The results suggested that Ca3, Ca4, and Ca5 stabilized the RTX domain. In conclusion, Ca3, Ca4, and Ca5 play a crucial role in the folding and stabilization of the RTX domain, which sustain the integrity of the overall AMS8 lipase structure.

International trade: Research of the reasons for the fall

2019 ◽  
pp. 79-91 ◽  
Author(s):  
V. S. Nazarov ◽  
S. S. Lazaryan ◽  
I. V. Nikonov ◽  
A. I. Votinov
Keyword(s):  
Growth Rate ◽  
International Trade ◽  
Exchange Rate ◽  
Global Economy ◽  
Structural Changes ◽  
Global Value Chains ◽  
Value Chains ◽  
Negative Contribution ◽  
Basic Commodity ◽  
The Impact

The article assesses the impact of various factors on the growth rate of international trade. Many experts interpreted the cross-border flows of goods decline against the backdrop of a growing global economy as an alarming sign that indicates a slowdown in the processes of globalization. To determine the reasons for the dynamics of international trade, the decompositions of its growth rate were carried out and allowed to single out the effect of the dollar exchange rate, the commodities prices and global value chains on the change in the volume of trade. As a result, it was discovered that the most part of the dynamics of international trade is due to fluctuations in the exchange rate of the dollar and prices for basic commodity groups. The negative contribution of trade within global value chains in 2014 was also revealed. During the investigated period (2000—2014), such a picture was observed only in the crisis periods, which may indicate the beginning of structural changes in the world trade.

THE IMPACT OF UKRAINE'S EXCISE DUTY POLICY ON THE TRANSFORMATION PROCESSES OF THE TOBACCO MARKET

2020 ◽  
Vol 2020 (10) ◽  
pp. 19-33
Author(s):  
Nadiia NOVYTSKA ◽  
◽  
Inna KHLIEBNIKOVA ◽  
Keyword(s):  
Structural Changes ◽  
Tax Avoidance ◽  
Transformation Process ◽  
State Regulation ◽  
Tobacco Products ◽  
Excise Duty ◽  
Increasing Demand ◽  
High Level ◽  
The Impact ◽  
Transformation Processes

The market of tobacco products in Ukraine is one of the most dynamic and competitive. It develops under the influence of certain factors that cause structural changes, therefore, the aim of the article is to conduct a comprehensive analysis of transformation processes in the market of tobacco and their alternatives in Ukraine and identify the factors that cause them. The high level of tax burden and the proliferation of alternative products with a potentially lower risk to human health, including heating tobacco products and e-cigarettes, are key factors in the market’s transformation process. Their presence leads to an increase in illicit turnover of tobacco products, which accounts for 6.37% of the market, and the gradual replacement of cigarettes with alternative products, which account for 12.95%. The presence on the market of products that are not taxed or taxed at lower rates is one of the reasons for the reduction of excise duty revenues. According to the results of 2019, the planned indicators of revenues were not met by 23.5%. Other reasons for non-fulfillment of excise duty revenues include: declining dynamics of the tobacco products market; reduction in the number of smokers; reorientation of «cheap whites» cigarette flows from Ukraine to neighboring countries; tax avoidance. Prospects for further research are identified, namely the need to develop measures for state regulation and optimization of excise duty taxation of tobacco products and their alternatives, taking into account the risks to public health and increasing demand of illegal products.

Effekt of blood flow shutdown on the vein damage when exposed to HIFU

2017 ◽  
pp. 46-50
Author(s):  
Н.Н. Петрищев ◽  
Д.Ю. Семенов ◽  
А.Ю. Цибин ◽  
Г.Ю. Юкина ◽  
А.Е. Беркович ◽  
...  
Keyword(s):  
Blood Flow ◽  
Structural Changes ◽  
Focused Ultrasound ◽  
Vena Cava ◽  
Posterior Wall ◽  
High Intensity Focused Ultrasound ◽  
Vein Wall ◽  
Ultrasound Exposure ◽  
Isolated Segment ◽  
The Impact

The purpose. In the study we investigated the impact of the partial blood flow shutdown on structural changes in the rabbit vena cava posterior wall after exposure to high-intensity focused ultrasound (HIFU). Methods. Ultrasound Exposure: frequency of 1.65 MHz, the ultrasound intensity in the focus of 13.6 kW/cm, the area of the focal spot 1 mm, continuous ultrasound, exposure for 3 seconds. Results. Immediately after HIFU exposure all layers of the vein wall showed characteristic signs of thermal damage. A week after exposure structural changes in the intima, media and adventitia was minimal in the part of vessel with preserved blood flow, and after 4 weeks the changes were not revealed. A week after HIFU exposure partial endothelium destruction, destruction of myocytes, disorganization and consolidation of collagen fibers of the adventitia were observed in an isolated segment of the vessel, and in 4 weeks endothelium restored and signs of damage in media and adventitia persisted, but were less obvious than in a week after exposure. Conclusion. The shutdown of blood flow after exposure to HIFU promotes persistent changes in the vein wall. Vein compression appears to be necessary for the obliteration of the vessel, when using HIFU-technology.

Recent Advances of In-Silico Modeling of Potent Antagonists for the Adenosine Receptors

2019 ◽  
Vol 25 (7) ◽  
pp. 750-773 ◽  
Author(s):  
Pabitra Narayan Samanta ◽  
Supratik Kar ◽  
Jerzy Leszczynski
Keyword(s):  
Drug Targets ◽  
Biological Activities ◽  
Scoring Function ◽  
Md Simulations ◽  
Energy Calculation ◽  
Binding Modes ◽  
Macromolecular Systems ◽  
In Silico Modeling ◽  
Mathematical Algorithms ◽  
The Impact

The rapid advancement of computer architectures and development of mathematical algorithms offer a unique opportunity to leverage the simulation of macromolecular systems at physiologically relevant timescales. Herein, we discuss the impact of diverse structure-based and ligand-based molecular modeling techniques in designing potent and selective antagonists against each adenosine receptor (AR) subtype that constitutes multitude of drug targets. The efficiency and robustness of high-throughput empirical scoring function-based approaches for hit discovery and lead optimization in the AR family are assessed with the help of illustrative examples that have led to nanomolar to sub-micromolar inhibition activities. Recent progress in computer-aided drug discovery through homology modeling, quantitative structure-activity relation, pharmacophore models, and molecular docking coupled with more accurate free energy calculation methods are reported and critically analyzed within the framework of structure-based virtual screening of AR antagonists. Later, the potency and applicability of integrated molecular dynamics (MD) methods are addressed in the context of diligent inspection of intricated AR-antagonist binding processes. MD simulations are exposed to be competent for studying the role of the membrane as well as the receptor flexibility toward the precise evaluation of the biological activities of antagonistbound AR complexes such as ligand binding modes, inhibition affinity, and associated thermodynamic and kinetic parameters.

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