Here, we present an updated version of iPPI-DB, our manually curated database of PPI modulators. In this release, the data model, the graphical interface and the tools to query the database have been completely redesigned. We used Chemaxon MarvinJS and JChem library to support this development. We added new PPI modulators, new PPI targets, and extended our focus to stabilizers of PPIs as well. Finally, we introduce a web application relying on crowdsourcing for the maintenance of the database. This application can be used outside of our group to collaboratively maintain iPPI-DB within a community of curators.

1. Use of Chemaxon MarvinJS and JChem library to
support the development of a new web application
for iPPI-DB
Olivier Sperandio
Chemoinformatics & Proteochemometrics Group
Unité de Bioinformatique Structurale
CNRS UMR 3528
Institut Pasteur
Chemaxon Webinars
May 27th 2020
1

2. Outline
• Introduction
• Last developments on iPPI-DB
• Future directions
2

3. Introduction
3

4. Nero & al, (2014), Nat Rev Cancer., Oncogenic protein interfaces: small molecules, big challenges.
Maccaron & al, (2011), Nat Rev Drug Discov., Impact of high-throughput screening in biomedical research.
• Small molecule - LMW ?
• Chemical space
• Privileged substructures
• Physico-chemistry
• ADME/Tox, PAINS
• Fragments
• Libraries
• PPI target ?
• Networks, Pathways
• Structural properties
• Dynamics
• Interface
• Binding cavities
• Druggability
PPI a challengeable class of therapeutic targets
• Target/LMW?
• Screening (HTS/VLS)
• Affinity prediction
• Interactions
• Compatibilities
• SAR
4
Whitty A. Nature Chemical Biology. 2006
• Difficulty to find non-peptide (Low Molecular Weight) compounds that
modulate PPI targets. Low hit rate on experimental screenings or high
false positive rate (e.g. HTS conventional target ≈ 0.1% vs PPI ≈ 0.01%)
➔ Not all PPIs are meant to become targets (as in therapeutic target)
➔ Not all PPI targets are equally suited for small molecule modulation
➔ Chemical libraries not designed for PPI
• Wealth of potential therapeutic targets
• Numerous implications in nearly all cellular compartments and various
pathologies. Special interest in infectious diseases (host/pathogen)

5. PPI a challengeable class of therapeutic targets
5
Nero & al, (2014), Nat Rev Cancer., Oncogenic protein interfaces: small molecules, big challenges.
Maccaron & al, (2011), Nat Rev Drug Discov., Impact of high-throughput screening in biomedical research.
• Small molecule - LMW ?
• Chemical space
• Privileged substructures
• Physico-chemistry
• ADME/Tox, PAINS
• Fragments
• Libraries
• PPI target ?
• Networks, Pathways
• Structural properties
• Dynamics
• Interface
• Binding cavities
• Druggability
• Target/LMW?
• Screening (HTS/VLS)
• Affinity prediction
• Interactions
• Compatibilities
• SAR
Whitty A. Nature Chemical Biology. 2006
• Difficulty to find non-peptide (Low Molecular Weight) compounds that
modulate PPI targets. Low hit rate on experimental screenings or high
false positive rate (e.g. HTS conventional target ≈ 0.1% vs PPI ≈ 0.01%)
➔ Not all PPIs are meant to become targets (as in therapeutic target)
➔ Not all PPI targets are equally suited for small molecule modulation
➔ Chemical libraries not designed for PPI
• Wealth of potential therapeutic targets
• Numerous implications in nearly all cellular compartments and various
pathologies. Special interest in infectious diseases (host/pathogen)

6. Venetoclax has just been
approved by the FDA
Venetoclax is a BH3-mimetic
and acts as a Bcl-2 inhibitor. It
blocks the anti-apoptotic B-cell
lymphoma-2 (Bcl-2) protein,
leading to programmed cell
death of CLL cells.
It is an ABT-737 analog whose
identification was first made
possible using NMR and
fragment-based design
Be inspired by success stories…
6

7. Chemical space analysis using
knowledge-based methods
iPPI
non iPPI
Learning Gain of knowledge
7

8. Last developments on iPPI-DB
8
http://ippidb.pasteur.fr/compounds/

9. iPPI-DB
9
• iPPI-DB (www.ippidb.cdithem.fr)
• Source
• Litterature (PubMed), world patents
• Hand curated by medicinal chemists
• Criteria
• Potency: IC50, Ki, Kd, EC50 < 30 μM
• Clear data on PPI targets
• Publications
• Labbé et al.(2013). Drug Discov Today
• Labbé et al.(2016). Nucleic Acids Res

10. iPPI-DB
• New designed web application for querying (MarvinJS & JChem)
• Web application for maintenance (MarvinJS & JChem)
• New data
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11. iPPI-DB
• New designed web application for querying (MarvinJS & JChem)
• Web application for maintenance (MarvinJS & JChem)
• New data
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12. A new query interface empowered by MarvinJS and JChem
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13. 13

14. 14

15. 15

16. iPPI-DB
• New designed web application for querying
• Web application for maintenance
• New data
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17. 17

18. 18

19. 19

20. 20

21. Future directions
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http://ippidb.pasteur.fr/compounds/

22. Future directions
• Considering the target itself
• Offering better functionalities to mine information
• Cross reference target and compounds even more efficiently
22

23. Acknowledgement
C&P Group
Alexandra Moine-Franel
C3BI HUB
Hervé Ménager
Rachel Torchet
Fabien Mareuil
BIS Unit
Michael Nilges
Arnaud Blondel
Guillaume Bouvier
PF-CCB
Fabrice Agou
Karen Druart
Bryan Brancotte
Luis Checa Ruano