What else can you do with the Markush cartridge?
Tracking chemical series for project teams
Anna Pelliccioli Ph.D., Gregory Landrum Ph.D.,
NIBR Informatics
Novartis Institutes for BioMedical Research
Budapest, ChemAxon UGM 2015
The Problem
 Medicinal chemists frequently use the idea of the “Series” as an
organizing principle.
 A compound belongs to a Series if its structure contains a particular
substructure or scaffold
 Scaffold definitions are ‘in the Chemist’s head’ or in some local files
 Learnings/decisions from Med Chem projects are typically associated
with the individual series.
 Series-level knowledge stays with scientists or, at best, in slide decks
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| Chemaxon UGM 2015 | Anna Pelliccioli | 19.05.2015 | Tracking chemical series for project teams | Business Use Only
Capturing the relationships among structures and series
Series A
Series B
Series C
1) Typical full article covering SAR around a
lead; 2) Review article
covering the latest developments across
compound classes; 3) Case study
outlining the history of a single molecule
reaching clinical stages of development.
The terms “screening hit” and “candidate” are
placeholders for chemical
entry points of any kind (including compounds
from other projects) and
desired end points that may be defined in many
different ways
Martin Stahl1,* and Sabine Baier,
ChemMedChem, published online 2015
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| Chemaxon UGM 2015 | Anna Pelliccioli | 19.05.2015 | Tracking chemical series for project teams | Business Use Only
The Compound Series and Favorites Project (CSF)
 Provide scientists with a shared space to store scaffold definitions and
most significant compounds (Favorites).
 Structures should be searchable within the new application
 Scientists should be able to annotate structures and scaffolds to capture
their learnings
 Everything should be accessible from other applications (like Spotfire)
via web services
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| Chemaxon UGM 2015 | Anna Pelliccioli | 19.05.2015 | Tracking chemical series for project teams | Business Use Only
An aside
 All structures and data in this presentation are taken from public data sources:
• Neil R. Curtis, Janusz J. Kulagowski, Paul D. Leeson, Mark P. Ridgill, Frances Emms, Stephen B. Freedman, Shil Patel,
Smita Patel, 1999, 'Synthesis and sar of 2- and 3-substituted 7-azaindoles as potential dopamine D4 ligands', Bioorganic &
Medicinal Chemistry Letters, vol. 9, no. 4, pp. 585-588
• Thomas R. Belliotti, Wouter A. Brink, Suzanne R. Kesten, John R. Rubin, David J. Wustrow, Kim T. Zoski, Steven Z.
Whetzel, Ann E. Corbin, Thomas A. Pugsley, Thomas G. Heffner, Lawrence D. Wise, 1998, 'Isoindolinone enantiomers
having affinity for the dopamine D4 receptor', Bioorganic & Medicinal Chemistry Letters, vol. 8, no. 12, pp. 1499-1502
• Christian Haubmann, Harald Hübner, Peter Gmeiner, 1999, 'Piperidinylpyrroles: Design, synthesis and binding properties of
novel and selective dopamine D4 receptor ligands', Bioorganic & Medicinal Chemistry Letters, vol. 9, no. 21, pp. 3143-3146
• Hubert H. M. Van Tol, James R. Bunzow, Hong-Chang Guan, Roger K. Sunahara, Philip Seeman, Hyman B. Niznik, Olivier
Civelli, 1991, 'Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine',
Nature, vol. 350, no. 6319, pp. 610-614
• Jalaj Arora, Michel Bordeleau, Laurence Dube, Keith Jarvie, Lucy Mazzocco, Jack Peragine, Ashok Tehim, Ian Egle, 2005,
'N-[(3S)-1-Benzylpyrrolidin-3-yl]-(2-thienyl)benzamides: Human dopamine D4 ligands with high affinity for the 5-HT2A
receptor', Bioorganic & Medicinal Chemistry Letters, vol. 15, no. 23, pp. 5253-5256
 Chemical structures exported from ChEMBL 19
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| Chemaxon UGM 2015 | Anna Pelliccioli | 19.05.2015 | Tracking chemical series for project teams | Business Use Only
CSF – the system
 Web-based front end:
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Bootstrap + JQuery
ChemDraw
Avalon toolkit for structure rendering
Calls out to multiple NIBR services
 CSF Service Layer:
• Java-based REST services
• RDKit for structure validation
 Database:
• Oracle + JChem + Markush extensions
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| Chemaxon UGM 2015 | Anna Pelliccioli | 19.05.2015 | Tracking chemical series for project teams | Business Use Only
CSF – the home page
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| Chemaxon UGM 2015 | Anna Pelliccioli | 19.05.2015 | Tracking chemical series for project teams | Business Use Only
Project Overview
Three series
Scaffold
Compound
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| Chemaxon UGM 2015 | Anna Pelliccioli | 19.05.2015 | Tracking chemical series for project teams | Business Use Only
Series overview
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| Chemaxon UGM 2015 | Anna Pelliccioli | 19.05.2015 | Tracking chemical series for project teams | Business Use Only
Detail Page and Path
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Detail Page and Path
source(s)
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Detail Page and Path
links
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Detail Page and Path
tags
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Tags
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Detail Page and Path
notes
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Detail Page and Path
reasoning
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Markush features
Several Markush features can
be used to define scaffolds
Not all features are supported:
depends on what the cartridge
can store as a target and what
our internal renderer can display
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Supported Markush features
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Adding compound/scaffold
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Checking for unsupported generic features
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Adding sources
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Search + Markush
Finds both
compounds and
scaffolds
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Search + Markush - alternative
structure search + other criteria
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CSF Integration in NIBR software landscape
Making it easy to add content to CSF and reuse it
Spotfire
DART
Scaffolds
Use scaffolds to
construct a DART
query
CSF
Scaffolds
Compounds
Compounds
Use scaffolds to run
multiple substructure
search
Series definition
HTSExplorer
CAST
Compounds
Compounds
PowerPoint
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Integration with other tools: Spotfire
Selecting scaffolds/compounds
Lists populated from
CSF’s service layer
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Integration with other tools: Spotfire
Editing, renaming
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Integration with other tools: Spotfire
Using the
scaffolds
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Integration – Add to CSF
Add to CSF
Add selected NVPs to CSF project
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Integration – Add to CSF
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Acknowledgements
 Project team
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Manuel Schwarze
Recca Chatterjee
Darina Nikolaeva
Mikhail Rybalkin
Roman Bolshev
 Advisory Team
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Mark Burfoot
John Davies
Jeremy Jenkins
Greg Paris
Tim Smith
 Acceptance Team
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Rohan Beckwith
Natalie Dales
Stefanie Flohr
Greg Hollingworth
Patrick Lee
Wolfgang Miltz
Ansgar Schuffenhauer
 Others
• Nico Pulver
• Guido Koch
• Hans Widmer
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