In a collaboration with ChemAxon we have developed a web-based interface for searching, browsing and managing chemical information. The system was designed to accommodate to capture the information that users stored in various documents in local files(like pdf, ppt slides, as images etc.). These bits of information were not centrally available, and when people moved on, this data was lost. ChemAxon’s JChem Cartridge and its Markush extensions and Document to Database tool enabled us to collect this data. It serves a good basis for future developments too. When developing this new interface, we focused on ease of use, maintainability, and flexibility.

1. What else can you do with the Markush cartridge?
Tracking chemical series for project teams
Gregory Landrum Ph.D., Anna Pelliccioli Ph.D.
NIBR Informatics
Novartis Institutes for BioMedical Research
Basel
ChemAxon UGM 2014 Cambridge, MA

2. 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.
• “We were unable to achieve selectivity with series A”
• “Series B has metabolic liabilities”
• “We decided to start lead-optimization activities with series C”
§ Series-level knowledge stays with scientists or, at best, in slide decks

3. 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

4. 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.

5. CSF – the system
§ Web-based front end:
• 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

6. CSF – the home page

7. Project Overview
Three series
Compound
Scaffold

8. Series overview

9. Detail Page and Path

10. Detail Page and Path
reasoning

11. Detail Page and Path
source(s)

12. Adding sources

13. Detail Page and Path
tags

14. Tags

15. Detail Page and Path
links

16. Detail Page and Path
notes

17. Adding compound/scaffold

18. 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

19. Supported Markush features

20. Checking for unsupported generic features

21. Search + Markush
Finds both
compounds and
scaffolds

22. Search + Markush - alternative
structure search + other criteria

23. Integration with other tools: Spotfire
Selecting scaffolds/compounds
Lists populated from
CSF’s service layer

24. Integration with other tools: Spotfire
Editing, renaming

25. Integration with other tools: Spotfire
Using the scaffolds

26. Acknowledgements
§ Project team
• Anna Pelliccioli
• Manuel Schwarze
• Recca Chatterjee
• Mikhail Rybalkin
• Roman Bolshev
§ Acceptance Team
• Natalie Dales
• Stefanie Flohr
• Greg Hollingworth
• Patrick Lee
• Wolfgang Miltz
• Ansgar Schuffenhauer
§ Advisory Team
• Mark Burfoot
• John Davies
• Jeremy Jenkins
• Greg Landrum
• Greg Paris
• Tim Smith
§ Others
• Nico Pulver
• Guido Koch
• Hans Widmer
§ ChemAxon
• Andras Volford