CEFIC LRI Tools – Ambit 1.21 Nina Jeliazkova Ideaconsult Ltd. Sofia, Bulgaria.

CEFIC LRI Tools – Ambit 1.21

Nina JeliazkovaIdeaconsult Ltd. Sofia,

Bulgaria

29.6.2007 QSAR Awareness Day, JRC, Ispra,Italy

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Outline Ambit overview Demo :

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

2. Complex query in the database –retrieve data meeting multiple criteria from Ambit database

3. 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 LanguageChemical Markup Language (CML) (CML) acknowledged method of encoding chemical data in XML acknowledged method of encoding chemical data in XML Is being adopted by a large number of chemical organisations, from Is being adopted by a large number of chemical organisations, from

government, through commercial to academia. government, through commercial to academia. The choice of CML for the internal format makes the database The choice of CML for the internal format makes the database

independent of the software which is able to access it, in contrast to independent of the software which is able to access it, in contrast to some proprietary solutions.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 system’s 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 Online:Query 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

AMBITDatabase main window consists of following areas:

Task bar on the left; Molecule browser

(top right); Molecule data tabs

(bottom right); Fast SMILES entry pa

nel (top);

Status bar at the bottom.

Standalone application available at http://ambit.acad.bg/downloads


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Demo:

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

2. Complex query in the database –retrieve data meeting multiple criteria from Ambit database

3. 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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The following window appears Check Read descriptors row

The following window appears: Check following descriptors :

XLogPDescriptor WeightDescriptor CrossectionalDiameterDescript

or MaximumDiameterDescriptor


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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 6/23/07,13:23 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 > <NSC> 2596

> <CrossSectionalDiameterDescriptor [Angstrom]> 2.4897

> <XLogPDescriptor> 1.7530

> <MaximumDiameterDescriptor [Angstrom]> 8.1759

> <SMILES> O=CCCCCC

> <AQUIRE> LC50=22000,ug/L Pimephales promelas LC50=22000,ug/L Pimephales promelas

> <CasRN> 66-25-1

> <WeightDescriptor> 100.0888


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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 > 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 > 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 > 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 > 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 < 4.5 Molecular weight < 1100 Cross sectional diameter < 17.4 Å Maximum diameter < 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 “<” sign. Double click on the next

column and enter 4.5 Repeat with descriptors:

WeightDescriptor (Molecular weight) < 1100

CrosssectionalDiameterDescriptor (crossectional diameter) < 17.4

MaximumDiameterDescriptor (maximum diameter or maximum length) < 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 Endpoint=“ER

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.

Thank you!

Questions?

CEFIC LRI Tools – Ambit 1.21 Nina Jeliazkova Ideaconsult Ltd. Sofia, Bulgaria.

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