George Papadatos - Knime Tutorial

Day 4: KNIME Practical
George Papadatos, ChEMBL group, EMBL-EBI

Francis Atkinson, ChEMBL group, EMBL-EBI
Outline
Introduction to KNIME
Basic components
Desktop, nodes, dialogs, workflows
Demo
Compound selection for focused screening
Read chemical data

Calculate properties
Apply drug- and lead- likeness filters
Remove nasty compounds
Pick diverse molecules
Visualize results and plot properties
Exercises 1 & 2 (hands-on)
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Resources for Computational Drug Discovery
Are there KNIME users among us?

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What is KNIME?
KNIME = Konstanz Information Miner

Developed at University of Konstanz in Germany
Desktop version available free of charge (Open Source)
Modular platform for building and executing workflows using
predefined components, called nodes
Core functionality available for tasks such as standard data
mining, analysis and manipulation
Extra features and functionality available in KNIME through
extensions from various groups and vendors
Written in Java based on the Eclipse SDK platform
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KNIME resources
Web pages (documentation)
www.knime.org | tech.knime.org | tech.knime.org/installation-0
Downloads
knime.org/download-desktop
Community forum
tech.knime.org/forum
Books and white papers

knime.org/node/33079
Myself
georgep@ebi.ac.uk
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What can you do with KNIME?

Data manipulation and analysis
File & database I/O, sorting, filtering, grouping, joining, pivoting
Data mining / machine learning

R, WEKA, KNIME, interactive plotting
Chemoinformatics
Conversions, similarity, clustering, (Q)SAR analysis, MMPs, reaction
enumeration
Scripting integration
R, Perl, Python, Matlab, Octave, Groovy
Reporting
So much more
Bioinformatics, HTS & image analysis, network & text mining
Marketing, bid data and business analytics
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Community contribution nodes

http://tech.knime.org/community
Chemoinformatics
ChEMBL and ChEBI (EBI) SureChEMBL nodes coming soon!
CDK (EBI), RDKit (Novartis), Indigo (GGA), ErlWood (Eli Lilly), Enalos
(NovaMechanics)
Bioinformatics
HCS (MPI), NGS (Konstanz), Image analysis
Text mining
Palladian
Integration
Python, Perl, R, Groovy, Matlab (MPI), PDB web services client (Vernalis)
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Installation & updates

Download and unzip KNIME
No further setup required
Additional nodes after first launch
knime.ini contains arguments & parameters for launch
New software (nodes) from update sites

http://tech.knime.org/update/community-contributions/release
Workflows and data are stored in a workspace

/Users/georgep/knime/workspace_mac_new

C:\knime_2.8.2\workspace
Customization in: FilePreferencesKNIME
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KNIME Workbench
Auto-layout Execute Execute all nodes
Node description
tabs
workflow projects
favorite nodes
public server
workflow editor
node repository
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outline
console
KNIME nodes: Overview

Node = basic processing unit of KNIME workflow which performs a particular task
Title
Input port(s) on the left of icon

Output port(s) on the right of icon
Icon
Status display (traffic lights)
Sequence number
Red (not ready)
Amber (ready)
Green (executed)
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Blue bar during execution

(with percentage or flashing)
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Right-click menu
To configure and
execute the node,
display the output
views, edit the
node, and display
data for the ports
KNIME nodes: Dialogs

Double click to configure
Configuration menus for
selected nodes
Explicit column type
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An example completed workflow

Workflows can be imported and exported as .zip files
With or without the underlying data
File Import KNIME workflow
File Export KNIME workflow
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Any questions so far?

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1.
2.
3.
4.
5.
6.
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Read chemical data

Calculate phys/chem properties
Apply drug- and lead-likeness filters
Apply more filters (e.g. remove solubility liabilities)
Apply substructural filters (PAINS subset)
Pick diverse molecules
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The objective
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First steps - I
Locate the directory with todays
material
1
2
Copy and paste it to your desktop

You can take it with you too
Open the presentation file

Import the
FocusedScreeningSelection.zip to
KNIME
Menu File Import workflow
to KNIME
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First steps - II
Open a new workflow
Right click on the workflow projects area
1
2
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Part 1: Reading chemical data
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SDF Reader
.\data\SMDC_cleaned_nodups.sdf
1
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Inspect the structures
Right click on the node
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Molecule to RDKit
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Part 2: Property-based filtering
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Descriptor Calculation
1
2
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Java Snippet
.\code\Lipinski.txt
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Numeric Row Splitter
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Inspect the Lipinski fails

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Java Snippet
.\code\Oprea.txt
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Inspect the Oprea fails

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Inspect the Solubility fails

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Part 3: Substructure-based filtering
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Molecule to Indigo
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File reader
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.\data\PAINS_clean_half.sdf
Query Molecule to Indigo
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Inspect the SMARTS rules
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Chunk Loop Start
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Substructure Matcher
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Loop End
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Inspect matched structures

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Reference Row Filter
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Part 4: Diversity picking and plotting
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RDKit Fingerprint
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Inspect the fingerprints

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RDKit Diversity Picker
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2D/3D Scatterplot
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Inspect the plot

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Exercise 1
Read an sd file with drug information from ChEMBL

Inspect the structures and their properties
Select only drugs that were released after 1990 (First Approval)
Select only drugs that target human (Homo sapiens)
How many drugs remain now?
Save the workflow
Tips
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Open a new workflow

Use the SDF Reader node
Use the Numeric Row Splitter node to filter on First Approval >= 1990
Use the Nominal Value Row filter node to filter on Organism = Homo
sapiens
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Exercise 2
Continue from your previous workflow

Calculate MW and logP of the drug compounds
Generate a scatter plot of MW and logP
Can you see any compounds with high MW and logP?
Tips
Use the Molecule to RDKit node
Use the RDKit Descriptor Calculator node
Include the SlogP and ExactMW descriptors
Use the 2D/3D Scatterplot node
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Any questions? Last chance!

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Conclusions
Typical scenario
KNIME
Open and free
Data analysis
Chemoinformatics toolkits
Erl Wood, RDKit, Indigo, CDK, etc.
Lots of other functionality
More advanced KNIME on Friday around lunch time
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Further reading
Open data and tools
1. Irwin, J. J.; Sterling, T.; Mysinger, M. M.; Bolstad, E. S.; Coleman, R. G., ZINC:
A free tool to discover chemistry for biology. Journal of Chemical Information
and Modeling 2012 ASAP.
2. Saubern, S.; Guha, R.; Baell, J. B., KNIME workflow to assess PAINS filters in
SMARTS format. Comparison of RDKit and Indigo cheminformatics libraries.
Molecular Informatics 2011, 30, (10), 847-850.
3. Barnes, M. R.; Harland, L.; Foord, S. M.; Hall, M. D.; Dix, I.; Thomas, S.;
Williams-Jones, B. I.; Brouwer, C. R., Lowering industry firewalls: precompetitive informatics initiatives in drug discovery. Nature Reviews Drug
Discovery 2009, 8, (9), 701-708.
4. Berthold, M. R.; Cebron, N.; Dill, F.; Gabriel, T. R.; Ktter, T.; Meinl, T.; Ohl, P.;
Sieb, C.; Thiel, K.; Wiswedel, B., KNIME: The Konstanz Information Miner. In
Data Analysis, Machine Learning and Applications, Preisach, C.; Burkhardt, H.;
Schmidt-Thieme, L.; Decker, R., Eds. Springer: Berlin, 2008; pp 319-326.
5. Tiwari, A.; Sekhar, A. K. T., Workflow based framework for life science
informatics. Computational Biology and Chemistry 2007, 31, (5-6), 305-319.
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Further reading
High throughput screening
1. Bajorath, J., Integration of virtual and high-throughput screening. Nature
Reviews Drug Discovery 2002, 1, (11), 882-894.
2. Harper, G.; Pickett, S. D.; Green, D. V. S., Design of a compound
screening collection for use in High Throughput Screening. Combinatorial
Chemistry & High Throughput Screening 2004, 7, (1), 63-70.
Lead- and drug-likeness

1. Chuprina, A.; Lukin, O.; Demoiseaux, R.; Buzko, A.; Shivanyuk, A., Drug- and
lead-likeness, target class, and molecular diversity analysis of 7.9 million
commercially available organic compounds provided by 29 suppliers. Journal of
Chemical Information and Modeling 2010, 50, (4), 470-479.
2. Lipinski, C. A., Lead- and drug-like compounds: the rule-of-five revolution. Drug
Discovery Today: Technologies 2004, 1, (4), 337-341.
3. Oprea, T. I.; Davis, A. M.; Teague, S. J.; Leeson, P. D., Is there a difference
between leads and drugs? A historical perspective. Journal of Chemical
Information and Computer Sciences 2001, 41, (5), 1308-1315.
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Further reading
Physicochemical properties and drug discovery
1. Brstle, M.; Beck, B.; Schindler, T.; King, W.; Mitchell, T.; Clark, T., Descriptors,
physical properties, and drug-likeness. Journal of Medicinal Chemistry 2002, 45,
(16), 3345-3355.
2. Hill, A. P.; Young, R. J., Getting physical in drug discovery: A contemporary
perspective on solubility and hydrophobicity. Drug Discovery Today 2010, 15,
(15/16), 648-655.
3. Leeson, P. D.; Springthorpe, B., The influence of drug-like concepts on decisionmaking in medicinal chemistry. Nature Reviews Drug Discovery 2007, 6, (11), 881890.
Structural alerts in HTS

1. Baell, J. B.; Holloway, G. A., New substructure filters for removal of Pan Assay
Interference Compounds (PAINS) from screening libraries and for their exclusion in
bioassays. Journal of Medicinal Chemistry 2010, 53, (7), 2719-2740.
2. Rishton, G. M., Reactive compounds and in vitro false positives in HTS. Drug
Discovery Today 1997, 2, (9), 382-384.
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Further reading
Similarity and diversity
1. Ashton, M.; Barnard, J.; Casset, F.; Charlton, M.; Downs, G.; Gorse, D.; Holliday,
J.; Lahana, R.; Willett, P., Identification of diverse database subsets using
property-based and fragment-based molecular descriptions. Quantitative
Structure-Activity Relationships 2002, 21, (6), 598-604.
2. Bender, A.; Glen, R. C., Molecular similarity: a key technique in molecular
informatics. Organic and Biomolecular Chemistry 2004, 2, 3204-3218.
3. Gorse, A.-D., Diversity in medicinal chemistry space. Current Topics in Medicinal
Chemistry 2006, 6, (1), 3-18.
4. Maldonado, A.; Doucet, J.; Petitjean, M.; Fan, B.-T., Molecular similarity and
diversity in chemoinformatics: From theory to applications. Molecular Diversity
2006, 10, (1), 39-79.
5. Rogers, D.; Hahn, M., Extended-connectivity fingerprints. Journal of Chemical
Information and Modeling 2010, 50, (5), 742-754.
6. Schuffenhauer, A.; Brown, N., Chemical diversity and biological activity. Drug
Discovery Today: Technologies 2006, 3, (4), 387-395.
7. Willett, P.; Barnard, J. M.; Downs, G. M., Chemical similarity searching. Journal
of Chemical Information and Computer Sciences 1998, 38, (6), 983-996.
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Day 4: KNIME Practical

George Papadatos, ChEMBL group, EMBL-EBI
Francis Atkinson, ChEMBL group, EMBL-EBI

George Papadatos - Knime Tutorial

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Day 4: KNIME Practical

George Papadatos, ChEMBL group, EMBL-EBI

Read chemical data

Exercises 1 & 2 (hands-on)

Resources for Computational Drug Discovery

Are there KNIME users among us?

Resources for Computational Drug Discovery

KNIME = Konstanz Information Miner

Resources for Computational Drug Discovery

Books and white papers

Resources for Computational Drug Discovery

What can you do with KNIME?

Data mining / machine learning

Resources for Computational Drug Discovery

Community contribution nodes

Resources for Computational Drug Discovery

Installation & updates

New software (nodes) from update sites

Workflows and data are stored in a workspace

Customization in: FilePreferencesKNIME

Resources for Computational Drug Discovery

Auto-layout Execute Execute all nodes

Resources for Computational Drug Discovery

KNIME nodes: Overview

Input port(s) on the left of icon

Blue bar during execution

Resources for Computational Drug Discovery

KNIME nodes: Dialogs

Explicit column type

Resources for Computational Drug Discovery

An example completed workflow

Resources for Computational Drug Discovery

Any questions so far?

Resources for Computational Drug Discovery

Compound selection for focused screening

Read chemical data

Resources for Computational Drug Discovery

Resources for Computational Drug Discovery

Copy and paste it to your desktop

Open the presentation file

Resources for Computational Drug Discovery

Resources for Computational Drug Discovery

Part 1: Reading chemical data

Resources for Computational Drug Discovery

Resources for Computational Drug Discovery

Inspect the structures

Right click on the node

Resources for Computational Drug Discovery

Resources for Computational Drug Discovery

Any questions so far?

Resources for Computational Drug Discovery

Part 2: Property-based filtering

Resources for Computational Drug Discovery

Resources for Computational Drug Discovery

Resources for Computational Drug Discovery

Numeric Row Splitter

Resources for Computational Drug Discovery

Inspect the Lipinski fails

Resources for Computational Drug Discovery

Resources for Computational Drug Discovery

Numeric Row Splitter

Resources for Computational Drug Discovery

Inspect the Oprea fails

Resources for Computational Drug Discovery