Automated Information Extraction and Structure−Activity Relationship Analysis of Cytochrome P450 Substrates

Yamashita, Fumiyoshi; Feng, Chunlai; Yoshida, Shuya; Itoh, Takayuki; Hashida, Mitsuru

doi:10.1021/ci100334z

Cited by 18 publications

(30 citation statements)

References 22 publications

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“…P450s were already the subject of many QSAR studies (Ekins et al, 1999;Lewis et al, 2001;Riley et al, 2001;Wanchana et al, 2003;Hansch et al, 2004;Mao et al, 2006;Gleeson et al, 2007;Yamashita et al, 2008Yamashita et al, , 2011 as well as inhibitor/noninhibitor classification studies (Jensen et al, 2007;Choi et al, 2009;Cheng et al, 2011). For large ADME/Tox characterization panels, it has been repeatedly found that molecular size plays a major, defining role.…”

Section: Resultsmentioning

confidence: 99%

Activity-Limiting Role of Molecular Size: Size-Dependency of Maximum Activity for P450 Inhibition as Revealed by qHTS Data

Buchwald¹

2014

Drug Metab Dispos

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Analysis of a large number of data on cytochrome P450 (P450) inhibition obtained from quantitative high-throughput screening assays from the PubChem BioAssay Database clearly indicates that molecular size has an important activity-limiting role for datasets focused on drug-like compounds (PubChem BioAssay Identifier [AID] 1851) as well as for datasets also incorporating a wider range of environmental chemicals (AIDs 410, 899, 883, 891, and 884). Maximum inhibitory activity increases with size for small enough structures then plateaus and begins to show a decreasing trend for larger structures. Log-scaled maximum median inhibitory concentration (pIC 50 ) as a function of molecular size could be fitted well with a bilinear model (LinBiExp), and the shape of the curve is quite similar across five P450 isozymes (CYP1A2, 2C9, 2C19, 2D6, and 3A4) with a turning-point of maximum inhibition around 300-500 Da. While the present size-based approach cannot account for the variability of activity in general, using data for a very large number of compounds, it still provides an intuitive interpretation of the maximum P450-inhibitory activity obtainable for a given molecular size and highlights the presence of an "optimum" size range.

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Section: Resultsmentioning

confidence: 99%

Activity-Limiting Role of Molecular Size: Size-Dependency of Maximum Activity for P450 Inhibition as Revealed by qHTS Data

Buchwald¹

2014

Drug Metab Dispos

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“…Based on trees from Lewis et al [34]., Terfloth et al [35]., Yamashita et al [36]. and Zhang et al [37].…”

Section: Decision Tree For Cyp Isoform Predictionmentioning

confidence: 99%

Precursors for cytochrome P450 profiling breath tests from an in silico screening approach

et al. 2014

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The family of cytochrome P450 enzymes (CYPs) is a major player in the metabolism of drugs and xenobiotics. Genetic polymorphisms and transcriptional regulation give a complex patientindividual CYP activity profile for each human being. Therefore, personalized medicine demands easy and non-invasive measurement of the CYP phenotype. Breath tests detect volatile organic compounds (VOCs) in the patients' exhaled air after administration of a precursor molecule. CYP breath tests established for individual CYP isoforms are based on the detection of 13 CO 2 or 14 CO 2 originating from CYP-catalyzed oxidative degradation reactions of isotopically labeled precursors.We present an in silico work-flow aiming at the identification of novel precursor molecules, likely to result in VOCs other than CO 2 upon oxidative degradation as we aim at label-free precursor molecules. The ligand-based work-flow comprises five parts: (1) CYP profiling was encoded as a decision tree based on 2D molecular descriptors derived from established models in the literature and validated against publicly available data extracted from the DrugBank. (2) Likely sites of metabolism were identified by reactivity and accessibility estimation for abstractable hydrogen radical. (3) Oxidative degradation reactions (O-and N-dealkylations) were found to be most promising in the release of VOCs. Thus, the CYP-catalyzed oxidative degradation reaction was encoded as SMIRKS (a programming language style to implement reactions based on the SMARTS description) to enumerate possible reaction products. (4) A quantitative structure property relation (QSPR) model aiming to predict the Henry constant H was derived from data for 488 organic compounds and identifies potentially VOCs amongst CYP reaction products.(5) A blacklist of naturally occurring breath components was implemented to identify marker molecules allowing straightforward detection within the exhaled air.

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“…Information extraction methods applied to extract structured data from publications have been studied extensively in the past in fields that include biology (BarbosaSilva et al, 2010, Corney et al, 2004, Meurs et al, 2011, chemistry (Na et al, 2010, Yamashita et al, 2011, biomedicine (Bundschus et al, 2008, Crowley et al, 2010, Pestian et al, 2007, text summarisation (Lin and Hovy, 2000) and e-learning (Monachesi et al, 2009). A review of these previous efforts is provided in this section.…”

Section: Related Workmentioning

confidence: 99%

“…Furthermore, similar approaches (ontology-based GATE gazetteer and relation extraction using pre-defined rules, and machine-learning) have been applied with mixed success to publications in the bioinformatics field (Barbosa-Silva et al, , Bundschus et al, 2008, Corney et al, 2004, Crowley et al, 2010, Meurs et al, 2011, Na et al, 2010, Pestian et al, 2007, Yamashita et al, 2011. Further examples are provided in the following paragraphs.…”

Section: Related Workmentioning

confidence: 99%

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A Semantic e-Science Platform for 20th Century Paint Conservation

Odat¹

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Throughout the twentieth century, artists in Australia and across the Southeast AsiaPacific region have enthusiastically embraced new materials (synthetic media, new pigments, dyes and additives). But compared to traditional artists' paints, these new materials have affected paint handling and paint stability. These new materials have also resulted in a lack of understanding of the preservation issues associated with the resulting artworks. As a result, today's collectors, curators and conservators are confronted with significant material-based preservation questions associated with 20 th century art/paint preservation -but they lack the sustained and integrated knowledge-base to inform their decision making.In order to understand the causes of paint degradation and the best preservation and treatment approaches, conservators need access to a wide range of distributed and cross-disciplinary datasets.  Use a number of case studies to evaluate OPPRA's ability to capture the detailed workflows and outputs associated with paint conservation experiments (e.g., sampling method, experimental processes and characterisation data); Apply and optimise a combination of semantic tagging and machine learning approaches to extract structured knowledge (compliant with OPPRA) from freetext publications on paint conservation -so it can be shared, integrated, compared and re-used; Evaluate OPPRA's ability to integrate experimental datasets, structured knowledge extracted from free-text publications and external public relevant databases (e.g., on paint chemistry), to answer a set of advanced, exemplar (SPARQL) queries specified by art conservators; Evaluate OWL-DL for inferencing and extracting new facts from the integrated knowledge base (generated from integrating experimental data capture, structured knowledge extracted from past publications and public relevant databases) in order to answer advanced queries specified by art conservators.4

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Automated Information Extraction and Structure−Activity Relationship Analysis of Cytochrome P450 Substrates

Cited by 18 publications

References 22 publications

Activity-Limiting Role of Molecular Size: Size-Dependency of Maximum Activity for P450 Inhibition as Revealed by qHTS Data

Activity-Limiting Role of Molecular Size: Size-Dependency of Maximum Activity for P450 Inhibition as Revealed by qHTS Data

Precursors for cytochrome P450 profiling breath tests from an in silico screening approach

A Semantic e-Science Platform for 20th Century Paint Conservation

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