CEFIC LRI Tools Ambit 1'21

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CEFIC LRI Tools Ambit 1.21

• Nina Jeliazkova
• Ideaconsult Ltd. Sofia, Bulgaria

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Outline

• Ambit overview
• Demo
• Finding basic information about a query compound
  in the database
• Complex query in the database retrieve data
  meeting multiple criteria from Ambit database
• Import data from EURAS Gold standard
  Bioconcentration database

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Introduction why Ambit ?

• Limited free, publicly accessible,
  methodologically transparent software was
  identified as one of the roadblocks for
  broadening use of in-silico methods (ICCA
  Workshop in Setubal 2002, OECD)
• Realization that efficient use of existing
  information on chemicals requires better ways for
  
• Storage
• standardized formats, computer automated
  verification of structures, capability to store
  large amounts of data
• Taking advantage of rapidly evolving field of
  data mining and extraction of relevant information

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IT strategy

• Ambit - building blocks for Decision Support
  System
• High emphasis on
• interoperability for plug and play
• Flexibility modular design
• Transparency
• Open source, relying on open standards. Open
  source software lowers the user barrier,
  facilitates the dissemination activities and
  enables the reproducibility of models and results
• The cheminformatics functionality relies on the
  open source Java library The Chemistry
  Development Kit http//cdk.sourceforge.net/
• The software is based on MySQL database
  (www.mysql.com), which is the most popular open
  source relational database.
• Chemical Markup Language (CML)
• acknowledged method of encoding chemical data in
  XML
• Is being adopted by a large number of chemical
  organisations, from government, through
  commercial to academia.
• The choice of CML for the internal format makes
  the database independent of the software which is
  able to access it, in contrast to some
  proprietary solutions.

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IT strategy

• Desktop installation MySQL database and
  standalone application (AmbitDatabaseTools) on
  the same PC
• Intranet installation MySQL database on a server
  and standalone application (AmbitDatabaseTools)
  on the user PCs
• Internet installation My SQL Database and web
  server (JSP and Servlets), Web browser as user
  interface

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Ambit overview

• The AMBIT database
• stores chemical structures, their identifiers
  such as CAS, INChI numbers attributes such as
  molecular descriptors, experimental data together
  with test descriptions, and literature
  references. The database can also store QSAR
  models. In addition the software can generate a
  suite of 2D and 3D molecular descriptors.
• can be searched by identifiers, attribute value
  or range, experimental data value or range, user
  defined structure and substructure, structural
  similarity
• AMBIT database contains over 450 000 chemical
  compounds with data imported from over a dozen
  databases http//ambit.acad.bg/ambit/stats/.
  The number of compounds is growing all the time
  and one the of systems great strengths is that
  any dataset can be imported for comparison and
  analysis. AMBITDatabaseTools 1.21 allows the user
  to create a local database and to import his own
  sets of chemical compounds.
• AMBIT Discovery performs chemical grouping and
  assesses the applicability domain of a QSAR
  offering a variety of methods including using
  different approaches to similarity assessments
  statistical that rely on descriptor space
  approaches based on mechanistic understanding
  and approaches based on structural similarity.
• ECB QMRF inventory a tailored version of Ambit
  database (under development). Will store
  information in QMRF. Large effort on
  standardization

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AMBIT Database Today
Not restricted to these datasets! Any dataset can
be imported. (e.g. DSSTox, AQUIRE, LLNA )
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AMBIT Database Schema
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AMBIT Online Similarity search
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AMBIT OnlineQuery result
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Links to other databases example KEGG
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Information about QSAR models
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Search AQUIRE database online
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Search EURAS Bioconcentration database online
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Ambit Database Tools 1.21
Standalone application available at
http//ambit.acad.bg/downloads

• AMBITDatabase main window consists of following
  areas
• Task bar on the left
• Molecule browser (top right)
• Molecule data tabs (bottom right)
• Fast SMILES entry panel (top)
• Status bar at the bottom.

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Demo

• Finding basic information about a query compound
  in the database
• Complex query in the database retrieve data
  meeting multiple criteria from Ambit database
• Import data from EURAS Gold standard
  Bioconcentration database

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Exercise 1. Finding basic information about a
query compound in the database

• Launch AmbitDatabaseTools 1.20
• Start menu/ All Programs/ CEFIC-LRI/Ambit 1.20

Ambit database tools main screen. Various tasks
can be started from the menu options at the left
panel. This exercise uses Search / CAS RN menu to
lookup for compound with specific CAS RN
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Exercise 1a. Lookup by CAS RN

• An input box appears
• Enter 66-25-1 and click OK.
• The result appears in top panel (Molecule
  browser)
• Click on 3D tab to view the 3D structure
• Further processing save, calculate descriptors,
  etc.

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Exercise 1b. Retrieve descriptors

• The objective of this exercise is to retrieve
  values of several descriptors from the database.
  The descriptors we are interested are
• LogP
• Crossectional diameter
• Maximum diameter
• Molecular weight
• Use Molecule/Advanced data retrieval menu

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Exercise 1b. Retrieve descriptors

• The following window appears
• Check Read descriptors row
• The following window appears
• Check following descriptors
• XLogPDescriptor
• WeightDescriptor
• CrossectionalDiameterDescriptor
• MaximumDiameterDescriptor

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Exercise 1b. Retrieve descriptors

• The results appear in Descriptors tab
• Further processing save, etc.

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Exercise 1c. Retrieve AQUIRE data

• Use Molecule/AQUIRE menu to retrieve toxicity
  data for hexaldehyde
• The results can be observed in bottom panel,
  EXPERIMENTAL data tab. Click on each row to view
  more details.
• Save to a file using File/Save menu (sdf, csv,
  xls, txt)

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SDF file for hexaldehyde

• CDK 6/23/07,1323 19 18 0 0 0 0 0 0 0
  0999 V2000 -0.0187 1.5258 0.0104 C 0 0
  0 0 0 0 0 0 0 0 0 0
• 0.0021 -0.0041 0.0020 C 0 0 0 0 0
  0 0 0 0 0 0 0
• 1.4167 2.0553 -0.0004 C 0 0 0 0 0
  0 0 0 0 0 0 0
• -1.4333 -0.5336 0.0129 C 0 0 0 0 0
  0 0 0 0 0 0 0
• 1.3963 3.5622 0.0079 C 0 0 0 0 0
  0 0 0 0 0 0 0
• 6 18 1 0 0 0 0
• 6 19 1 0 0 0 0
• M END
• gt ltNSCgt
• 2596
• gt ltCrossSectionalDiameterDescriptor Angstromgt
• 2.4897
• gt ltXLogPDescriptorgt
• 1.7530
• gt ltMaximumDiameterDescriptor Angstromgt

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XLS file for hexaldehyde
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Exercise 2. Complex queries Use Ambit database
to retrieve data that meet multiple criteria

• Use Search options /options menu to configure
  desired searches
• Switch to Similarity tab and set 0,7 for Tanimoto
  threshold (we will be searching for structures
  with Tanimoto similarity gt 0.7)

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Exercise 2a. Similarity search

• Use Search/Structure search menu to invoke
  advanced query window
• Draw dimetylphtalate as shown at the figure
• Click Similarity button
• Browse the 7 compounds found (in Molecule
  Browser)
• Go to Search/options and lower threshold to 0.6
• Use Search/Structure search/Similarity again with
  the same compound

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Exercise 2a. Similarity search

• Now there are 156 compounds with Tanimoto
  similarity gt 0.6
• We will be using Molecule/Save as dataset menu
  to store the query results into the database
• Hint you can store query results directly into
  database, without loading into Molecule Browser,
  by setting Search Options/Result destination
  DATABASE and then performing the query

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Database and datasets - background

• There can be many Ambit databases running on one
  MySQL server
• Within Ambit database the chemical compounds can
  be grouped in many subsets.
• Typically, one database consists of multiple
  subsets (datasets), corresponding to the origin
  of the data (e.g. the file used to import the
  compounds)
• The search results can be marked as a separate
  subset within Ambit database
• The search can be performed within entire Ambit
  database or just on a selected subset.
• This allows to use results of one query as a
  input to another and restrict the set of
  structures step by step

• Database server (MySQL)
• Ambit Database 1 (e.g. ambit)
• Dataset 1 (200 000 structures from NCI)
• Dataset 2 (600 structures from DSSTox EPA Fathead
  Minnow)
• Dataset 3 (AQUIRE)
• Dataset 4 (DSSTox carcinogenic potency data)
• Dataset 5 (EURAS Bioconcentration factor data)
• Dataset 6 (my similarity search results)
• Ambit Database 2 (e.g. test_database)
• Ambit Database N (e.g. my_secret_dataset)
• Other (non-Ambit) databases

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Exercise 2a. Similarity search

• Use Molecule/Save as dataset menu to store the
  query results into the database
• In the dialog box (as at right), add button
  to add a new entry for the dataset.
• Type in the name for the dataset (e.g.
  Similarity search Tanimoto gt 0.6)
• Click OK

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Exercise 2a. Similarity search

• Now the new dataset is available in the datasets
  list and can be used to restrict subsequent
  queries
• Use Search options/Dataset menu to select which
  dataset to be searched, select Similarity search
  Tanimoto gt 0.6 and click OK

Note this will not load any structures into
Molecule browser!
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Exercise 2b. Pre-set physicochemical profile

• The objective is to extract compounds that have
  physicochemical properties, relevant for
  bioaccumulation from the set of structurally
  similar compounds found by previous query.
• The recommended descriptors and ranges are
• LogP lt 4.5
• Molecular weight lt 1100
• Cross sectional diameter lt 17.4 Å
• Maximum diameter lt 43 Å

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Exercise 2b. Pre-set physicochemical profile

• Use Search/Structure search menu
• The window with options for structure,
  descriptors and experimental data queries
  appears.
• Click on Descriptors icon to obtain a list of
  descriptors available in the database

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Exercise 2b. Pre-set physicochemical profile

• Select XLogP descriptor (click on first column
• Click on Condition column and select lt sign.
• Double click on the next column and enter 4.5
• Repeat with descriptors
• WeightDescriptor (Molecular weight) lt 1100
• CrosssectionalDiameterDescriptor (crossectional
  diameter) lt 17.4
• MaximumDiameterDescriptor (maximum diameter or
  maximum length) lt 43
• Click the Search button

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Exercise 2b. Pre-set physicochemical profile

• 123 out of the 156 structurally similar compounds
  have the predefined profile.
• The descriptor values can be inspected in the
  Descriptors tab

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Exercise 2c. Retrieve available toxicity data

• Use Search Options/Options menu to select he
  endpoint
• Select AQUIRE tab
• Select LC50 (Lethal concentration to 50 of test
  compounds) from the first list box

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Exercise 2c. Retrieve available toxicity data

• The next step is to tell the software we want to
  retrieve the data for all retrieved compounds
  (not only for the current structure). To do this
• Select Molecule processing tab
• Select Molecule Browser Current set of
  structures from the first list box

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Exercise 2c. Retrieve available toxicity data

• Use Molecule/AQUIRE menu to retrieve LC50 data
  for the current set of compounds
• Click Start button.

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Exercise 2c. Retrieve available toxicity data

• Browse the compounds to view AQUIRE data at the
  bottom panel
• Repeat the same procedure to retrieve BCF data
  from AQUIRE

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Exercise 2d. Retrieve available toxicity data
(ER Binding)

• Structure/Search menu
• Click experiments
• Select DSSTox-ERBinding
• Select EndpointER RBA
• Click Search

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Exercise 2d. Retrieve available toxicity data
(ER Binding)

• Browse ER Binding data, save results into file

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More exercises

• Batch search
• Import structures into database
• Import descriptors and experimental data (e.g.
  bioconcentration factor dataset)
• Import QSAR models
• Database processing
• Descriptor calculation
• Atom environments, Fingerprint, SMILES generation
• Create new (empty) database.
• Create users for the new database
• Import compounds

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Ambit - Summary

• AMBIT software is a set of libraries and tools,
  providing various chemoinformatics
  functionalities for data management.
• The AMBIT system consists of a database and
  functional modules allowing a variety of flexible
  searches and mining of the data stored in the
  database.
• The unique feature of AMBIT is the ability to
  store multifaceted information about chemical
  structures and provide a searchable interface
  linking these diverse components.

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Thank you!

• Questions?