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Find video protocols related to scientific articles indexed in Pubmed.
An unbiased approach to identify endogenous substrates of "histone" deacetylase 8.
ACS Chem. Biol.
PUBLISHED: 08-11-2014
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Despite being extensively characterized structurally and biochemically, the functional role of histone deacetylase 8 (HDAC8) has remained largely obscure due in part to a lack of known cellular substrates. Herein, we describe an unbiased approach using chemical tools in conjunction with sophisticated proteomics methods to identify novel non-histone nuclear substrates of HDAC8, including the tumor suppressor ARID1A. These newly discovered substrates of HDAC8 are involved in diverse biological processes including mitosis, transcription, chromatin remodeling, and RNA splicing and may help guide therapeutic strategies that target the function of HDAC8.
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Impact of stereospecific intramolecular hydrogen bonding on cell permeability and physicochemical properties.
J. Med. Chem.
PUBLISHED: 02-26-2014
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Profiling of eight stereoisomeric T. cruzi growth inhibitors revealed vastly different in vitro properties such as solubility, lipophilicity, pKa, and cell permeability for two sets of four stereoisomers. Using computational chemistry and NMR spectroscopy, we identified the formation of an intramolecular NH?NR3 hydrogen bond in the set of stereoisomers displaying lower solubility, higher lipophilicity, and higher cell permeability. The intramolecular hydrogen bond resulted in a significant pKa difference that accounts for the other structure-property relationships. Application of this knowledge could be of particular value to maintain the delicate balance of size, solubility, and lipophilicity required for cell penetration and oral administration for chemical probes or therapeutics with properties at, or beyond, Lipinski's rule of 5.
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Computational methods for early predictive safety assessment from biological and chemical data.
Expert Opin Drug Metab Toxicol
PUBLISHED: 11-04-2011
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The goal of early predictive safety assessment (PSA) is to keep compounds with detectable liabilities from progressing further in the pipeline. Such compounds jeopardize the core of pharmaceutical research and development and limit the timely delivery of innovative therapeutics to the patient. Computational methods are increasingly used to help understand observed data, generate new testable hypotheses of relevance to safety pharmacology, and supplement and replace costly and time-consuming experimental procedures.
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An investigation into pharmaceutically relevant mutagenicity data and the influence on Ames predictive potential.
J Cheminform
PUBLISHED: 09-02-2011
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In drug discovery, a positive Ames test for bacterial mutation presents a significant hurdle to advancing a drug to clinical trials. In a previous paper, we discussed success in predicting the genotoxicity of reagent-sized aryl-amines (ArNH2), a structure frequently found in marketed drugs and in drug discovery, using quantum mechanics calculations of the energy required to generate the DNA-reactive nitrenium intermediate (ArNH:+). In this paper we approach the question of what molecular descriptors could improve these predictions and whether external data sets are appropriate for further training.
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Avoidance of the Ames test liability for aryl-amines via computation.
Bioorg. Med. Chem.
PUBLISHED: 02-13-2011
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Aryl-amines are commonly used synthons in modern drug discovery, however a minority of these chemical templates have the potential to cause toxicity through mutagenicity. The toxicity mostly arises through a series of metabolic steps leading to a reactive electrophilic nitrenium cation intermediate that reacts with DNA nucleotides causing mutation. Highly detailed in silico calculations of the energetics of chemical reactions involved in the metabolic formation of nitrenium cations have been performed. This allowed a critical assessment of the accuracy and reliability of using a theoretical formation energy of the DNA-reactive nitrenium intermediate to correlate with the Ames test response. This study contains the largest data set reported to date, and presents the in silico calculations versus the in vitro Ames response data in the form of beanplots commonly used in statistical analysis. A comparison of this quantum mechanical approach to QSAR and knowledge-based methods is also reported, as well as the calculated formation energies of nitrenium ions for thousands of commercially available aryl-amines generated as a watch-list for medicinal chemists in their synthetic optimization strategies.
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Origins of regioselectivity and alkene-directing effects in nickel-catalyzed reductive couplings of alkynes and aldehydes.
J. Am. Chem. Soc.
PUBLISHED: 01-26-2010
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The origins of reactivity and regioselectivity in nickel-catalyzed reductive coupling reactions of alkynes and aldehydes were investigated with density functional calculations. The regioselectivities of reactions of simple alkynes are controlled by steric effects, while conjugated enynes and diynes are predicted to have increased reactivity and very high regioselectivities, placing alkenyl or alkynyl groups distal to the forming C-C bond. The reactions of enynes and diynes involve 1,4-attack of the Ni-carbonyl complex on the conjugated enyne or diyne. The consequences of these conclusions on reaction design are discussed.
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The chemical tuning of a weak zinc binding motif for histone deacetylase using electronic effects.
Chem Biol Drug Des
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The hydroxamic acid moiety is an effective metal-binding warhead for a variety of metalloenzyme targets of interest in drug-discovery. For the zinc-containing histone deacetylase enzymes in particular, this chemical group has been widely incorporated and studied in the clinic. An alternative chemical functionality for binding zinc is the ?-aminocarbonyl motif, which has been shown to bind to histone deacetylase enzymes. The current article explores the minimal binding site theoretical approach combined with structural knowledge to explore the ideal chemical substitution pattern of the ?-aminocarbonyl motif within HDAC8. The metal-binding strength of the group is predicted to be highly tunable to chemical substitution at the carbonyl and the ?-amino carbon. A fixed receptor model approach with a dispersion-corrected density functional, clearly discerned the effect of different substituents at both these positions using either a flexible or partially fixed ligand optimized in the presence of a fixed receptor model of the HDAC8 binding site. An electron donating substituent such as methyl at the C(?) in combination with NMe(2) substitution at the carbonyl position, similar to observed crystal structures, result in the optimal energetic profile for binding the zinc atom in the HDAC8 enzyme.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.