In silico methods
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Ten published DNA-based analytical methods aiming at detecting material of almond (Prunus dulcis) were in silico evaluated for potential cross-reactivity with other stone fruits (Prunus spp.), including peach, apricot, plum, cherry, sour cherry and Sargent cherry. For most assays, the analysis of nucleotide databases suggested none or insufficient discrimination of at least some stone fruits. On the other hand, the assay targeting non-specific lipid transfer protein (Röder et al., 2011, Anal Chim Acta 685:74-83) was sufficiently discriminative, judging from nucleotide alignments. Empirical evaluation was performed for three of the published methods, one modification of a commercial kit (SureFood allergen almond) and one attempted novel method targeting thaumatin-like protein gene. Samples of leaves and kernels were used in the experiments. The empirical results were favourable for the method from Röder et al. (2011) and a modification of SureFood allergen almond kit, both showing cross-reactivity <10(-3) compared to the model almond.
A review on applicability of in silico methods for toxicity testing by calculation for regulatory purposes, their survey and background of QSAR (Quantitative Structure-Activity Relationships) analysis are presented.
Regional deposition effects are important in the pulmonary delivery of drugs intended for the topical treatment of respiratory ailments. They also play a critical role in the systemic delivery of drugs with limited lung bioavailability. In recent years, significant improvements in the quality of pulmonary imaging have taken place, however the resolution of current imaging modalities remains inadequate for quantifying regional deposition. Computational Fluid-Particle Dynamics (CFPD) can fill this gap by providing detailed information about regional deposition in the extrathoracic and conducting airways. It is therefore not surprising that the last 15years have seen an exponential growth in the application of CFPD methods in this area. Survey of the recent literature however, reveals a wide variability in the range of modelling approaches used and in the assumptions made about important physical processes taking place during aerosol inhalation. The purpose of this work is to provide a concise critical review of the computational approaches used to date, and to present a benchmark case for validation of future studies in the upper airways. In the spirit of providing the wider community with a reference for quality assurance of CFPD studies, in vitro deposition measurements have been conducted in a human-based model of the upper airways, and several groups within MP1404 SimInhale have computed the same case using a variety of simulation and discretization approaches. Here, we report the results of this collaborative effort and provide a critical discussion of the performance of the various simulation methods. The benchmark case, in vitro deposition data and in silico results will be published online and made available to the wider community. Particle image velocimetry measurements of the flow, as well as additional numerical results from the community, will be appended to the online database as they become available in the future.
- MeSH
- absorpce v dýchacích cestách MeSH
- aerosoly chemie MeSH
- aplikace inhalační MeSH
- benchmarking metody MeSH
- biologické modely MeSH
- farmaceutická chemie metody MeSH
- hydrodynamika MeSH
- laryngální masky * MeSH
- lékové transportní systémy metody MeSH
- lidé MeSH
- nebulizátory a vaporizátory MeSH
- permeabilita MeSH
- plíce účinky léků MeSH
- počítačová simulace * MeSH
- prášky, zásypy, pudry chemie MeSH
- reologie MeSH
- velikost částic MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Arterial compliance (AC) is an important cardiovascular parameter characterizing mechanical properties of arteries. AC is significantly influenced by arterial wall structure and vasomotion, and it markedly influences cardiac load. A new method, based on a two-element Windkessel model, has been recently proposed for estimating AC as the ratio of the time constant T of the diastolic blood pressure decay and peripheral vascular resistance derived from clinically available stroke volume measurements and selected peripheral blood pressure parameters which are less prone to peripheral distortions. The aim of this study was to validate AC estimation using a virtual population generated by in silico model of the systemic arterial tree. In the second part of study, we analysed causal coupling between AC oscillations and variability of its potential determinants - systolic blood pressure and heart rate in healthy young human subjects. The pool of virtual subjects (n=3818) represented an extensive AC distribution. AC was estimated from the peripheral blood pressure curve and by the standard method from the aortic blood pressure curve. The proposed method slightly overestimated AC set in the model but both ACs were strongly correlated (r=0.94, p<0.001). In real data, we observed that AC dynamics was coupled with basic cardiovascular parameters variability independently of the autonomic nervous system state. In silico analysis suggests that AC can be reliably estimated by noninvasive method. The analysis of short-term AC variability together with its determinants could improve our understanding of factors involved in AC dynamics potentially improving assessment of AC changes associated with atherosclerosis process. Key words Arterial compliance, Cardiovascular model, Arterial blood pressure, Causal analysis, Volume-clamp photoplethysmography.
- MeSH
- arterie * fyziologie MeSH
- cévní rezistence fyziologie MeSH
- dospělí MeSH
- krevní tlak * fyziologie MeSH
- lidé MeSH
- mladý dospělý MeSH
- modely kardiovaskulární * MeSH
- počítačová simulace * MeSH
- poddajnost MeSH
- srdeční frekvence fyziologie MeSH
- tuhost cévní stěny fyziologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- validační studie MeSH
BACKGROUND: In recent years the number of natural products used as pharmaceuticals, components of dietary supplements and cosmetics has increased tremendously requiring more extensive evaluation of their pharmacokinetic properties. PURPOSE: This study aims at combining in vitro and in silico methods to evaluate the gastrointestinal absorption (GIA) of natural flavonolignans from milk thistle (Silybum marianum (L.) Gaertn.) and their derivatives. METHODS: A parallel artificial membrane permeability assay (PAMPA) was used to evaluate the transcellular permeability of the plant main components. A dataset of 269 compounds with measured PAMPA values and specialized software tools for calculating molecular descriptors were utilized to develop a quantitative structure-activity relationship (QSAR) model to predict PAMPA permeability. RESULTS: The PAMPA permeabilities of 7 compounds constituting the main components of the milk thistle were measured and their GIA was evaluated. A freely-available and easy to use QSAR model predicting PAMPA permeability from calculated physico-chemical molecular descriptors was derived and validated on an external dataset of 783 compounds with known GIA. The predicted permeability values correlated well with obtained in vitro results. The QSAR model was further applied to predict the GIA of 31 experimentally untested flavonolignans. CONCLUSIONS: According to both in vitro and in silico results most flavonolignans are highly permeable in the gastrointestinal tract, which is a prerequisite for sufficient bioavailability and use as lead structures in drug development. The combined in vitro/in silico approach can be used for the preliminary evaluation of GIA and to guide further laboratory experiments on pharmacokinetic characterization of bioactive compounds, including natural products.
- MeSH
- flavonoidy chemie farmakokinetika MeSH
- flavonolignany farmakokinetika MeSH
- intestinální absorpce účinky léků MeSH
- kvantitativní vztahy mezi strukturou a aktivitou * MeSH
- lidé MeSH
- membrány umělé MeSH
- ostropestřec mariánský chemie MeSH
- permeabilita buněčné membrány účinky léků MeSH
- počítačová simulace MeSH
- potravní doplňky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
This article is focused on the application of two types of docking software, AutoDock and DOCK. It is aimed at studying the interactions of a calcium-dependent bacterial lectin PA-IIL (from Pseudomonas aeruginosa) and its in silico mutants with saccharide ligands. The effect of different partial charges assigned to the calcium ions was tested and evaluated in terms of the best agreement with the crystal structure. The results of DOCK were further optimized by molecular dynamics and rescored using AMBER. For both software, the agreement of the docked structures and the provided binding energies were evaluated in terms of prediction accuracy. This was carried out by comparing the computed results to the crystal structures and experimentally determined binding energies, respectively. The performance of both docking software applied on a studied problem was evaluated as well. The molecular docking methods proved efficient in identifying the correct binding modes in terms of geometry and partially also in predicting the preference changes caused by mutation. Obtaining a reasonable in silico method for the prediction of lectin-saccharide interactions may be possible in the future.
- MeSH
- bakteriální adheziny genetika chemie MeSH
- financování organizované MeSH
- informatika MeSH
- kvarterní struktura proteinů MeSH
- lektiny genetika chemie MeSH
- ligandy MeSH
- molekulární modely MeSH
- molekulární sekvence - údaje MeSH
- monosacharidy chemie MeSH
- mutageneze cílená statistika a číselné údaje MeSH
- počítačová simulace MeSH
- Pseudomonas aeruginosa genetika chemie MeSH
- sekvence aminokyselin MeSH
- sekvenční homologie aminokyselin MeSH
- software MeSH
- termodynamika MeSH
- vápník chemie MeSH
- vazebná místa genetika MeSH
OBJECTIVES: The aim of this study was to detect endocrine disruption potential of selected bisphenols and phthalates, compare in silico prediction with results from two in vitro methods and bring up-to-date information on development of EU legislation, available in vitro methods and biomechanisms involved in endocrine disruption. MATERIAL AND METHODS: In silico approach based on the OECD QSAR Toolbox was used for prediction of estrogen receptor α binding. OECD TG 455 assay and a yeast-based YES/YAS assay was used to determine the interactions with human estrogen (ERα) and androgen receptors. RESULTS: In silico results predicted the screened phthalates as non binders and bisphenols as very strong binders of the ERα. In vitro results differed from in silico prediction in several cases but exhibited concordance mainly for strong binders of ERα. Most of the substances exhibited parallel activity (agonist-antagonist) on both estrogen and androgen receptors. Agonistic studies showed the effective concentration of 10% activity (EC10) from 5.0E-07 for strong agonists (e.g. BPC, BPTMC). Cytotoxicity was observed after 48 h exposure of S. cerevisiae to BPFL, BPG, BPM, BPTMC in concentrations starting at 3.6E-05 mol/l. CONCLUSION: Our results suggest multiple parallel interactions of tested compounds and emphasize the importance of determination of an appropriate battery of in vitro methods that will include more receptors and will be appropriate to target specific molecular mechanisms involved in endocrine disruption. Results in agonistic studies indicate agonistic potential and are supported by results of antagonistic studies with consideration of possible multiple interactions.
- MeSH
- alfa receptor estrogenů metabolismus MeSH
- androgenní receptory metabolismus MeSH
- androgeny metabolismus MeSH
- biotest metody MeSH
- endokrinní disruptory metabolismus MeSH
- estrogeny metabolismus MeSH
- lidé MeSH
- receptory pro estrogeny metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The effect of terminal GLY114* deletion on the binding affinity of the PA-IIL lectin toward L: -fucose was investigated. Both experimental (isothermal titration calorimetry) and computational (molecular dynamics simulations) methods have shown that the deletion mutation decreases the L-fucose affinity. It implies that the PA-IIL saccharide binding affinity is influenced by the dimerization of the lectin. A detailed analysis of computational data confirms the key role of electrostatic interactions in the PA-IIL/saccharide binding.
- MeSH
- bakteriální adheziny genetika chemie metabolismus MeSH
- Escherichia coli genetika MeSH
- financování organizované MeSH
- fukosa chemie metabolismus MeSH
- kalorimetrie metody MeSH
- kinetika MeSH
- kompetitivní vazba MeSH
- krystalizace MeSH
- kvarterní struktura proteinů MeSH
- lektiny genetika chemie metabolismus MeSH
- molekulární modely MeSH
- multimerizace proteinu MeSH
- mutace MeSH
- počítačová simulace MeSH
- Pseudomonas aeruginosa genetika metabolismus MeSH
- rekombinantní proteiny chemie metabolismus MeSH
- sekvenční delece MeSH
- terciární struktura proteinů MeSH
- termodynamika MeSH
- vazba proteinů MeSH
INTRODUCTION: Autoinflammatory diseases can cause irreversible tissue damage due to systemic inflammation. Recently, the Autoinflammatory Disease Damage Index (ADDI) was developed. The ADDI is the first instrument to quantify damage in familial Mediterranean fever, cryopyrin-associated periodic syndromes, mevalonate kinase deficiency and tumour necrosis factor receptor-associated periodic syndrome. The aim of this study was to validate this tool for its intended use in a clinical/research setting. METHODS: The ADDI was scored on paper clinical cases by at least three physicians per case, independently of each other. Face and content validity were assessed by requesting comments on the ADDI. Reliability was tested by calculating the intraclass correlation coefficient (ICC) using an 'observer-nested-within-subject' design. Construct validity was determined by correlating the ADDI score to the Physician Global Assessment (PGA) of damage and disease activity. Redundancy of individual items was determined with Cronbach's alpha. RESULTS: The ADDI was validated on a total of 110 paper clinical cases by 37 experts in autoinflammatory diseases. This yielded an ICC of 0.84 (95% CI 0.78 to 0.89). The ADDI score correlated strongly with PGA-damage (r=0.92, 95% CI 0.88 to 0.95) and was not strongly influenced by disease activity (r=0.395, 95% CI 0.21 to 0.55). After comments from disease experts, some item definitions were refined. The interitem correlation in all different categories was lower than 0.7, indicating that there was no redundancy between individual damage items. CONCLUSION: The ADDI is a reliable and valid instrument to quantify damage in individual patients and can be used to compare disease outcomes in clinical studies.
- MeSH
- dědičné zánětlivé autoimunitní nemoci komplikace diagnóza MeSH
- dítě MeSH
- dospělí MeSH
- familiární středomořská horečka komplikace diagnóza MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nedostatek mevalonátkinázy komplikace diagnóza MeSH
- odchylka pozorovatele MeSH
- periodické syndromy asociované s kryopyrinem komplikace diagnóza MeSH
- počítačová simulace MeSH
- registrace MeSH
- reprodukovatelnost výsledků MeSH
- stupeň závažnosti nemoci * MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- validační studie MeSH
