In Silico Identification of Protein Targets for Chemical Neurotoxins Using ToxCast In Vitro Data and Read-Across within the QSAR Toolbox

2020 ◽  
pp. 103-119
Author(s):  
Yaroslav G. Chushak ◽  
Jeffery M. Gearhart ◽  
Heather A. Pangburn ◽  
Hannah W. Shows
Keyword(s):  
In Silico ◽  
Protein Targets ◽  
In Silico Identification ◽  
Vitro Data ◽  
In Vitro Data

scholarly journals In silico identification of protein targets for chemical neurotoxins using ToxCast in vitro data and read-across within the QSAR toolbox

2018 ◽  
Vol 7 (3) ◽  
pp. 423-431 ◽  
Author(s):  
Y. G. Chushak ◽  
H. W. Shows ◽  
J. M. Gearhart ◽  
H. A. Pangburn
Keyword(s):  
In Silico ◽  
Protein Targets ◽  
In Silico Identification ◽  
Vitro Data ◽  
In Vitro Data

This study evaluates the application of QSAR Toolbox and ToxCast screening data to identify neurological targets for pyrethroids.

scholarly journals Insights and Perspectives on Emerging Inputs to Weight of Evidence Determinations for Food Safety: Workshop Proceedings

2013 ◽  
Vol 32 (6) ◽  
pp. 405-414 ◽  
Author(s):  
Heidi Bialk ◽  
Craig Llewellyn ◽  
Alison Kretser ◽  
Richard Canady ◽  
Richard Lane ◽  
...  
Keyword(s):  
Food Safety ◽  
In Silico ◽  
High Throughput Screening ◽  
Weight Of Evidence ◽  
Food Ingredient ◽  
Food Ingredients ◽  
Safety Assessments ◽  
Vitro Data ◽  
In Vitro Data

This workshop aimed to elucidate the contribution of computational and emerging in vitro methods to the weight of evidence used by risk assessors in food safety assessments. The following issues were discussed: using in silico and high-throughput screening (HTS) data to confirm the safety of approved food ingredients, applying in silico and HTS data in the process of assessing the safety of a new food ingredient, and utilizing in silico and HTS data in communicating the safety of food ingredients while enhancing the public’s trust in the food supply. Perspectives on integrating computational modeling and HTS assays as well as recommendations for optimizing predictive methods for risk assessment were also provided. Given the need to act quickly or proceed cautiously as new data emerge, this workshop also focused on effectively identifying a path forward in communicating in silico and in vitro data.

In vitro -In vivo- In silico Simulation of Experimental Design Based Optimized Curcumin Loaded Multiparticulates System

2018 ◽  
Vol 24 (30) ◽  
pp. 3576-3586
Author(s):  
Sima Singh ◽  
Afzal Hussain ◽  
Uma Ranjan Lal ◽  
Nisar Sayyad ◽  
Rajshekhar Karpoormath ◽  
...  
Keyword(s):  
Experimental Design ◽  
Drug Release ◽  
In Silico ◽  
Laser Scanning Microscopy ◽  
Enhanced Absorption ◽  
In Silico Simulation ◽  
Vitro Data ◽  
In Vitro Data

The present study focused to optimize dual coated multiparticulates using Box-Behnken Experimental Design and in-silico simulation using GastroPlusTM software. The optimized formulations (OB1 and OB2) were comparatively evaluated for particle size, morphological, in vitro drug release, and in vivo permeation studies. In silico simulation study predicted the in vivo performance of the optimized formulation based on in-vitro data. Results suggested that optimized formulation was obtained using maximum content of Eudragit FS30D and minimum drying time (2 min). In vitro data corroborated that curcumin release was completely protected from premature drug release in the proximal part of gastro intestinal tract and successfully released to the colon (95%) which was closely predicted (90.1 %) by GastroPlusTM simulation technique. Finally, confocal laser scanning microscopy confirmed the in-vitro findings wherein maximum intensity was observed with OB1 treated group suggesting successful delivery of OB1 to the colon for enhanced absorption as predicted in regional absorption profile in ascending colon (30.9%) and caecum (23.2%). Limited drug absorption was predicted in small intestine (1.5-8.7%). The successful outcomes of the research work minimized the release of curcumin in the upper gastric tract and the maximized drug access to the colon (pH 7.4) as prime concern.

Human-based computational and experimental investigation of disease mechanisms in mutation-specific hypertrophic cardiomyopathy

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
F Margara ◽  
Y Psaras ◽  
B Rodriguez ◽  
CN Toepfer ◽  
A Bueno-Orovio
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
In Silico ◽  
Calcium Transient ◽  
Calcium Sensitivity ◽  
Human Cardiomyocytes ◽  
Calcium Affinity ◽  
Myofilament Calcium Sensitivity ◽  
Vitro Data ◽  
In Vitro Data

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement 764738. British Heart Foundation Intermediate Basic Science Fellowship (FS/17/22/32644). Background The pathogenic TNNI3R21C/+ variant causes malignant hypertrophic cardiomyopathy (HCM) with high incidence of sudden cardiac death, even in individuals absent of hypertrophy. There is evidence to support a known biophysical defect in the protein, yet the cellular mechanisms that precipitate adverse clinical outcomes remain unclear. Purpose We aim to computationally model and map the TNNI3R21C/+ cellular phenotype observed in induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) to human disease, thereby explaining the key mechanisms driving HCM in TNNI3R21C/+ variant carriers.  Methods Wild-type (WT) and TNNI3R21C/+ iPSC-CMs were characterised by calcium transient analysis and direct sarcomere tracking to assess cellular contraction and relaxation. In-vitro data was used to inform the in-silico modelling of human cardiomyocytes. We constructed an in-silico population of WT adult cardiomyocytes and used it to transform the in-vitro data into corresponding adult phenotypes by means of a novel iPSC-to-adult data mapping. We tested the hypothesis that the abnormal TNNI3R21C/+ phenotype observed in iPSC-CMs would be explained by alterations in calcium affinity of troponin and increased myofilament calcium sensitivity.  Results Analysis of in-vitro iPSC-CM data showed that TNNI3R21C/+ cells exhibit increased contractility with slowed relaxation when compared to WT. They also exhibited a faster rise in the calcium transient with a slowed calcium decay in comparison to WT. The in-silico adult TNNI3R21C/+ phenotype from the iPSC-to-adult mapping replicated the abnormalities observed in iPSC-CMs. The WT in-silico population accurately covered the ranges of electromechanical biomarkers providing a representative cohort of physiological variability. The TNNI3R21C/+ calcium phenotype could be recovered by our in-silico mutant models. Simulation results suggest that calcium abnormalities in TNNI3R21C/+ are a direct consequence of abnormal calcium buffering by thin filaments, mediated by increases in calcium affinity of troponin and myofilament calcium sensitivity. The TNNI3R21C/+ phenotype could not be recovered if these two factors were considered in isolation. Corresponding contractility analyses of in-silico models showed that the calcium level changes caused by the TNNI3R21C/+ phenotype are associated with hypercontractility and diastolic dysfunction, well-known hallmarks of HCM, which were also observed in the iPSC-CM model of disease. Conclusions This study showcases human-based computational and experimental methodologies that unearth direct mechanistic explanations of phenotypes driven by the TNNI3R21C/+ HCM variant. We show that the TNNI3R21C/+ HCM-causing mutation exhibits multifactorial remodelling of troponin calcium affinity and myofilament calcium sensitivity. Unearthing mechanistic pathways in mutation-specific HCM will be key to develop effective pharmacological interventions for a wide variety of understudied variants.

In silico prediction of drug effects on human ventricular electrophysiology using the Virtual Assay software and comparison to in vitro data

2016 ◽  
Vol 81 ◽  
pp. 345-346
Author(s):  
Elisa Passini ◽  
Oliver Britton ◽  
Hua Rong Lu ◽  
David J. Gallacher ◽  
Jutta Rohrbacher ◽  
...  
Keyword(s):  
In Silico ◽  
Drug Effects ◽  
In Silico Prediction ◽  
Vitro Data ◽  
In Vitro Data

Early assessment of proarrhythmic risk of drugs using the in vitro data and single-cell-based in silico models: proof of concept

2016 ◽  
Vol 27 (2) ◽  
pp. 88-99 ◽  
Author(s):  
Mitra Abbasi ◽  
Ben G. Small ◽  
Nikunjkumar Patel ◽  
Masoud Jamei ◽  
Sebastian Polak
Keyword(s):  
Single Cell ◽  
In Silico ◽  
Proof Of Concept ◽  
Early Assessment ◽  
Proarrhythmic Risk ◽  
In Silico Models ◽  
Vitro Data ◽  
In Vitro Data

scholarly journals FutureTox II: In vitro Data and In Silico Models for Predictive Toxicology

2015 ◽  
Vol 143 (2) ◽  
pp. 256-267 ◽  
Author(s):  
Thomas B. Knudsen ◽  
Douglas A. Keller ◽  
Miriam Sander ◽  
Edward W. Carney ◽  
Nancy G. Doerrer ◽  
...  
Keyword(s):  
In Silico ◽  
Predictive Toxicology ◽  
In Silico Models ◽  
Vitro Data ◽  
In Vitro Data

scholarly journals Development of an adverse outcome pathway for cranio-facial malformations: A contribution from in silico simulations and in vitro data

2020 ◽  
Vol 140 ◽  
pp. 111303 ◽  
Author(s):  
Francesca Metruccio ◽  
Luca Palazzolo ◽  
Francesca Di Renzo ◽  
Maria Battistoni ◽  
Elena Menegola ◽  
...  
Keyword(s):  
In Silico ◽  
Adverse Outcome ◽  
Adverse Outcome Pathway ◽  
Vitro Data ◽  
In Vitro Data
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