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Structure Browser Information
The EPA DSSTox Structure-Browser, developed from available structure-viewing freeware and open-source programming tools (see Specifications& Acknowledgements), delivers a simple, easy-to-use structure-searching capability through the chemical inventory of published DSSTox Data Files. The DSSTox Structure-Browser application can be accessed directly from this website, or from the external websites of DSSTox Collaborators and others through a simple URL address link (see Accessing DSSTox Structure-Browser). Additional details of the DSSTox Structure-Browser options and operations are provided below:
Version 2.0 Enhancements ** Updated 12 August 2008
Note: The DSSTox Structure-Browser has been optimized for use in Microsoft Explorer. We caution that users may experience some problems (e.g., text wrapping) with other Internet Browsers (e.g., Mozilla FireFox) at this time. For more information on current Structure-Browser limitations and planned improvements, see Specifications.
New Users: For more information on the EPA DSSTox project, visit the DSSTox Home page.
Chemical text search options listed below offer various types of text searching through DSSTox Standard Chemical Fields in all or selected DSSTox Data Files. The text search option is limited to exact text matches (all or partial text) through existing DSSTox Data File content and, therefore, provides a much more limited search option than performing a structure/substructure/similarity search.
Note: DSSTox Data Files do not, as a rule, contain lists of chemical name synonyms or alternate/discontinued CAS RN, although occasionally these are provided in the various Note fields (ChemicalNote or Note_NAMEID).
Chemical Name: wildcard (*) enabled; case-insensitive
Searches full or partial chemical names (common or systematic names) contained in TestSubstance_ChemicalName and STRUCTURE_ChemicalName_IUPAC fields of DSSTox Data Files. Lists of chemical name synonyms are not provided in DSSTox Data Files. Wildcard character (*) option can be used to broaden name search. If a match is found in the DSSTox inventory, a broader structure search can be initiated. Sample entries:
Chloroprene
CAS RN: formatted or unformatted (with or without hyphens)
Searches for CAS Registry Numbers contained in the TestSubstance_CASRN field of DSSTox Data Files. If a match is found in the DSSTox inventory, a broader structure search can be initiated. Alternate or retired CAS RNs are not searched. A CAS RN Check is performed to determine if entered value represents a valid CAS RN; an error message is returned if invalid CAS RN is entered in search box. Sample entries:
InChI: case-sensitive, must be proceeded by standard "InChI=..." text
Searches for InChI (version 1) text-string representations of chemical structure contained in the STRUCTURE_InChI field of DSSTox Data Files (see More on InChI). An exact match can be used to initiate a broader structure search. Sample entry for Chloroprene [126-99-8]:
Note: Although InChI is a representation of chemical structure, this version of the DSSTox Structure-Browser only performs a text match search and does not automatically convert InChI directly to structure for a structure search; later versions will include this feature of automatic initiation of a broader structure search.
Formula: case-sensitive
Searches for full or partial empirical (molecular) formula contained in the STRUCTURE_Formula field of DSSTox Data Files. An exact match can be used to initiate a broader structure search. Sample entries:
Auto-detect: default selection, wildcard (*) enabled for Chemical Name only
Default selection automatically detects the type of chemical text entry as one of the 4 allowed types listed above, filtering detection in order of most sytematic/easily detected (InChI, CAS RN), to less systematic (Formula), to least systematic (Chemical Name). If the requirements of InChI, CAS RN, and Formula (which additionally checks for valid atomic symbols) are not met, then the entry is assumed to be a Chemical Name, without further validity checks.
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"Data Files to Search" Options
The DSSTox Structure-Browser is designed to search chemical/structure content through all or a portion of the published DSSTox Data File inventory. This is made possible because individual DSSTox Data Files are separately indexed within the system.
The default option is to search through "All DSSTox Files", i.e. the full list of published DSSTox Data Files.
Note: When the DSSTox Structure-Browser is accessed from external websites, through a URL link to the EPA server hosting the Structure-Browser application, the specifics of the URL will specify which DSSTox Data Files the Structure-Browser is to search through. A user can change this incoming default selection using this Data Files to Search options once they are in the browser. See Accessing the DSSTox Structure-Browser for more information.
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Chemical Structure Drawing Editor
Chemical Drawing Editor: 
The JME Molecular Editor
Example shown above has user-drawn structure for chlorobenzene. Once structure has been submitted for search, the original Search page will also compute and display the corresponding SMILES.
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SMILES: case-sensitive
SMILES are a text-based representation of chemical structure (see More on SMILES) but, unlike InChI codes, are not unique. Hence, a "SMILES" search first converts the SMILES code to a unique representation of "structure", this structure is displayed in the Chemical Structure Drawing Editor for user verification, and then the user has the option to initiate a structure search in the DSSTox Structure-Browser.
Example above shows SMILES entry for chlorobenzene. If the "Preview below" button is clicked, the corresponding drawn structure appears in the Chemical Structure Drawing Editor (see preceding graphic).
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Exact match: default option - on
If this option is checked, all "exact" structure matches to the query structure will be presented on the File Incidences search results page of the Structure-Browser. This search option ignores charge differences, stereo-specific information, and does not include equivalent tautomeric forms. Exact match results are displayed on the Search Details results page and listed separately by row if their DSSTox TestSubstance (Generic Substance ID) characteristics differ.
Substructure: default option - on
If this option is checked, all structures containing the query "substructure" will be presented on the File Incidences search results page of the Structure-Browser. This search option ignores charge differences and stereo-specific information. Substructure results are displayed on the Search Details results page and listed separately by row if their DSSTox TestSubstance (Generic Substance ID) characteristics differ. The user is cautioned that this search option can return exceedingly large numbers of search hits. To produce smaller numbers of hits, the user should use a larger or more specific substructure query.
Similarity: default option - on; Threshold default 80%
If this option is checked, a commonly employed "Tanimoto similarity coefficient" is used as a search filter, with the default threshold value of 80% similarity coefficient arbitrarily chosen to provide a reasonable capture rate of hits that are likely to have obvious similar structure characteristics when viewed by the user. All hits exceeding the chosen Threshold % similarity score will be presented on the File Incidences search results page of the Structure-Browser. Increasing the Threshold % will place more stringent criteria for similarity, producing fewer hits above the threshold, whereas decreasing the Threshold % will loosen the criteria for similarity, producing more hits, but of less obvious similarity. Similarity hits presented on the Search Details results will be listed along with their Tanimoto similarity score to provide the user an approximate sense of how similar the hit is perceived to be relative to the query structure. Note that a minimum number of hits (at least 10 structures) will be displayed, regardless of the threshold entered. Hence, in the event that fewer than 10 structure hits are produced above the chosen threshold, the adjusted threshold that produced the displayed 10 hits is shown.
** New to v2.0: A minimum of 10 structure match hits are presented on the File Incidences search results page, regardless of the chosen default threshold for similarity. The Similarity cutoff displayed under the "Results Type" header will be adjusted accordingly on the FIle Incidences page (e.g., the top 10 structure matches for "atrazine" structure search yields 12 substance hits, exceeding a similarlty of 51.2%).
Of the three Search Options, Similarity is capable of casting the broadest net in a search for chemical analogs as it is not restricted to the precise characteristics of the drawn chemical structure query. Adjusting the Threshold %, a user can calibrate how stringent the similarity metric, and how many hits are returned.
A Tanimoto similarity coefficient is computed based on comparison of binary "fingerprint" representations of all structures in the search inventory to the binary fingerprint of the query structure. Such fingerprints are generally computed from fragment decompositions of each molecule as follows:
Sab = c/(a+b-c)
c is number of "on" bits (matching) in both query and the target,
a is number of "on" bits in query (matching or not),
b is number of "on" bits in target (matching or not).Implementation of the Tanimoto similarity coefficient in the DSSTox Structure-Browser is described in Specifications.
A more general and technical discourse on similarity metrics, including Tanimoto coefficients, can be found at: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=eurekah.section.3798
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Searching at Generic Test Substance Level
The DSSTox Structure-Browser performs structure searches through the inventory of chemical substance records in DSSTox Data Files based on the contents of the STRUCTURE field, which is uniquely indexed by DSSTox_CID (Chemical ID). However, since different test substances (mixtures, different purity grades, etc.), which could have different toxicity characteristics, can share the same structure representation and DSSTox_CID, search results are presented to the user based on the more specific generic substance identifier, DSSTox_Generic_SID. (denoted "DSSTox Substance ID" on the "Search Details" page)
DSSTox_Generic_SID better discriminates test substance at a level nearly equivalent to the commonly employed CAS RN identifier, but also discriminates when no CAS RN are available, or when CAS RN do not discriminate different substances, such as when purity grades are known to differ. DSSTox_Generic_SID does not, however, discriminate test substance records that differ at the test sample level (e.g., lot, batch, manufacturer, plate number); hence our use of the term "Generic" in the field name. The DSSTox Record ID (DSSTox_RID) is a unique record identifier that does distinguish to the level of test sample, which is important for those DSSTox data files undergoing current testing (i.e., NTPHTS and TOXCST).
Listed on the File Incidences search results page, at the bottom of the table that includes the breakdown of search results according to DSSTox Data File, are the summarized totals for substance hits.
Total Unique Substance Hits = Total number of different DSSTox_Generic_SID 's occurring in each Search type column (i.e., Exact, Substructure, Similarity) across all listed data files.
Total Substance Hits = Total number of DSSTox_Generic_SID 's occurring in each Search type column (i.e., Exact, Substructure, Similarity) across all listed data files, counting all replicates of a DSSTox_Generic_SID found in different DSSTox data files.
The practical ramifications of displaying results by DSSTox_Generic_SID (listed as DSSTox Substance ID in figure below) are that test substance hits, even those sharing the same STRUCTURE or DSSTox_CID identifier, will be listed separately by DSSTox_Generic_SID in the same results line (with links to one or more DSSTox Data Files containing that same DSSTox_Generic_SID substance). An example of such a view from the Search Details page is shown below:
Note: The presentation of structure search results in the DSSTox Structure-Browser by DSSTox_Generic_SID differs significantly from PubChem, which groups substance results (defined by Source depositor, not by test substance characteristics) at the level of PubChem Chemical ID (PubChem CID), a structure identifier with a 1:1 correspondence to DSSTox_CID.
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Save Option
Print Option
Selecting the "Print" option uses the Internet browser print function to print the page being viewed; limitations of this print function will be browser-dependent and outside of our control.
Exporting Full DSSTox Data Files
All users of the DSSTox Structure-Browser should be aware that downloads of complete DSSTox Data Files (SD files or .xls data tables), along with documentation, are available from the DSSTox Website. These SD files are a primary product of the DSSTox Project and can be imported into any user-owned Chemical Relational Database (CRD) application to facilitate local structure-browsing and tailored data capture.
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Accessing DSSTox Structure-Browser from External Websites
http://www.epa.gov/dsstox_structurebrowser/. Extensions to the URL allow users to modify the parameters of the search. The general forms of the URL extension are:?dbs=[NAMEID]&hits=[search type]&thresh=[number]
?qtype=[query type]&qval=[query value]where dbs refers to DSSTox data file name (e.g., NTPBSI, IRISTR), and
where qtype can be any of the following: auto, name, cas, inchi, formula, smiles, cid, sid, inchikey (the last new to v2.0).
where NAMEID is the 6 letter DSSTox Data File NAMEID code, e.g., CPDBAS, EPAFHM, etc; the default entry is dbs=all. To search through more than one file, use the modification: ?dbs=NAMEID(1)-NAMEID(2)-NAMEID(3)For example:
To add modifiers to specify search default options and search threshold, use the additional qualifiers, e.g. hits=exc-sub-sim&thresh=60; the default entries are hit=all and thresh=80
For example:
**Note: Some characters in search strings may be reserved for special html interpretations; hence, it may be necessary to "escape" or "encode" a url-based query when storing it or sending it to a colleague. This is particularly true of SMILES, where alternative characters may be needed for commonly used symbols such as:
= ..... %3d
@ ... %40
# ... %23
[ ... %5b
] ... %5d
More information and guidance on these restrictions are available at: http://en.wikipedia.org/wiki/URL-encoding
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DSSTox Structure-Browser Specifications
The DSSTox Structure-Browser version 1.0 was developed using the following publicly available tools, scripting code, and applications:
Version 1.0 of the chemical structure search process is carried out using original Perl code designed by Tom Transue (Lockheed Martin - Contractor to the US EPA) with help from Joe Krahn (formerly Lockheed Martin - Contractor to the US EPA). Structures drawn or submitted as SMILES strings are first processed using the CDK toolkit to produce a "mol" file with an aromaticity model determined by CDK's implementation of Huckle's Rule. Perl code then establishes a compound's attributes or paths considering only heavy-atom (non-hydrogen) elements without consideration of charge or isotope and bond connectivity (including bond orders: 1,2,3, and "aromatic"). Each compound is assigned a set of attributes or paths consisting of linear paths (up to length 8), rings (up to 7-memeber), and atom centers (with 3 or more heavy-atom bond-partners). An original algorithm then compares paths generated from a query molecule to the 29,364 unique paths found in the 6,637 unique chemical structures found in the DSSTox data inventory (as of 15Aug2008) to determine a Tanimoto similarity coefficient and to determine candidates for superstructures of the query. A second algorithm confirms which of these candidates is in fact a superstructure and which are exact matches. Results are presented with a heavy use of client-side JavaScript to reduce network demand and improve performance. See Acknowledgements & Disclaimers.
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DSSTox Structure-Browser v2.0 Enhancements
The DSSTox Structure-Browser version 2.0 includes several new enhancements and features:
Expanded "link-in" options and user-defined limits
Users or external websites are able to directly access the DSSTox Structure-Browser Main Search Page, or File Incidences Search Results Page (resulting from a structure search), by simple extensions to the DSSTox Structure Browser URL. Features include:
For general format of the URL extensions and several examples, see: Accessing DSSTox Structure-Browser from External Websites
Minimum of 10 structure similarity hits displayed
A minimum of 10 structure match hits are presented on the File Incidences search results page, regardless of the chosen default threshold for similarity. The Similarity cutoff displayed under the "Results Type" header will be adjusted accordingly on the FIle Incidences page (e.g., the top 10 structure matches for "atrazine" structure search yields 12 substance hits, exceeding a similarlty of 51.2%). The purpose is to override the similarity threshold only in cases where too few structure search hits are returned.
New structure-based link-outs to external websites are provided (three are external to EPA and are currently active; the fourth, ACToR, will be activated as soon as this new EPA resource becomes publicly available, est. Sept 2008). These link-outs are intended to assist users in directly accessing structure-related content and capabilities on external public websites of potential interest to the DSSTox user community. The link-out corresponds to the displayed or indicated Query Structure on any of the DSSTox Structure Browser Search Results Pages (File Incidences, Search Details, Substance Results). Note that for the case where a text search (e.g., Chemical Name or CAS) produces a hit, the External Resources link-outs will be activated even though the initial File Incidences Search Results Page does not display a query structure (this requires a structure search resubmit, see below).
For more information on PubChem and in relation to the DSSTox Project, see Searching DSSTox Files in PubChem. Link-out from the DSSTox Structure Browser is based on the DSSTox field, PubChem_CID (PubChem Compound IDs), available for all registered DSSTox substances.
ChemSpider is a free on-line service providing access to millions of chemical structures, computed chemical properties, chemical resources, and integration to a multitude of other online services, including link-outs to DSSTox and PubChem. In addition, ChemSpider has recently used the EPA EPI (Estimation Programs Interface) Suite™ estimation model software to generate physical/chemical and environmental fate properties for its entire on-line inventory of over 20 million structures. Link-out from the DSSTox Structure Browser is based on InChIKey (conforming to ChemSpider conventions for InChIKey generation), available also as a DSSTox Standard Chemical Field, STRUCTURE_InChIKey
Lazy Structure-Activity Relationship (lazar) predictions are based on chemical structure and activity similarity calculations (activity-informed nearest neighbor approach) for a variety of summary toxicity endpoints. More information can be found on the Lazar Documentation page.
ACToR (Aggregated Computational Toxicology Resource) is a tool being developed within the EPA's National Center for Computational Toxicology to manage large scale sets of assay associated with the EPA ToxCast project, as well as publicly available inventories and toxicology data on chemicals of interest to the EPA. The resource is slated for public internet release in September, 2008. For more information, visit the EPA ACToR Home Page. Link-out from the DSSTox Structure Browser will be based on ACToR CIDs corresponding to DSSTox registered substances.
Structure "hit" resubmit feature
As an extension of a normal structure search, this option allows a user to automatically submit any structure "hit" resulting from a text or structure search to a new structure search (exact/substructure/similarity). This feature provides structure look-up capability through the entire DSSTox Data File structure inventory and, additionally, circumvents the need for a user to recall and draw a structure to submit for a structure search. In addition, the feature enables structure analog hits resulting from the substructure or similarity search to be submitted for a structure search, i.e. converting the structure hit to the Query structure which then enables External Resource link-outs to be accessed.
An example is shown below in which a Search for Chemical Name = atrazine, was originally submitted, and Details of the Exact matches (1 Hit) was chosen on the File Incidences Page.
The text hit retrieves a structure for "Atrazine" that is listed as being present in 7 DSSTox Data Files. The yellow triangle (SS) in the lower right corner of the structure display (shown above) can be clicked to submit this structure for a standard search (i.e., exact, substructure, and similarity) across the originally specified DSSTox Data Files. The results of this structure search will display the structure in the Query box and will display similarity hits to this structure as shown below, any one of which could be resubmitted for a structure search. If the user wishes to edit this automatically generated Query structure and resubmit, they can return to the Search Tab Page where the Atrazine structure will now appear in the Chemical Drawing Editor window.
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Planned Upgrades & Future Enhancements
The following upgrades and features are planned for future versions of the DSSTox Structure-Browser:
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DSSTox Structure-Browser Acknowledgements
The DSSTox Structure-Browser was developed by Tom Transue (Lockheed Martin - Contractor to the US EPA), with design assistance from Ann Richard (EPA) and Michael Brown (Lockheed Martin). Others (from the US EPA or from Lockheed Martin, Contractors to the US EPA) who assisted with initial stages of development or in advisory/technical/review aspects of the DSSTox Structure-Browser implementation include: Maritja Wolf, Michael Uhl, Joseph Mack, Joseph Krahn, Joseph Retzer, Robert Kavlock, Christine Russom, Rob McCauley, Tommy Cathey, and Todd Plessel. The developers would also like to thank Peter Ertl and Novartis for making JME
We would also like to acknowledge collaborators who are currently using the URL link-in capability to access the DSSTox Structure Browser Main page, or to directly access the File Incidences Results page with a structure submission from their websites
http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm
http://www.chemspider.com/
http://lazar.in-silico.de/To provide feedback or to report problems with the DSSTox Structure-Browser, please complete and submit the User Feedback Form. See also Disclaimers.
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The DSSTox Structure-Browser was developed using publicly available resources to enhance and extend the utility of the freely-downloadable DSSTox Data Files. However, the EPA DSSTox Project and Contractor-support code developers make no explicit or implied guarantees concerning the operation or results of the DSSTox Structure-Browser. The DSSTox Structure-Browser code has been reviewed within EPA's Office of Research and Development and approved for posting on the EPA DSSTox website. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
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