"Targeting and tinkering with interaction networks", Barcelona, 14.04.2008

1. From protein
interaction networks to
human phenotypes
Michael Kuhn
Peer Bork lab, EMBL Heidelberg
mkuhn@embl.de

2. Genomic context methods to predict protein interactions
Dandekar et al. TIBS 98 Enright et al. Nature 99
Overbeek et al. PNAS 99 Pellegrini et al. PNAS 99 Marcotte et al. Science 99
Korbel et al., Nat. Biotechn. 04 Morett et al., Nat. Biotechn. 03
Korbel, von Mering, Jensen, Bork Nat. Biotech. 22(04)911

3. Towards probabilistic function predictions
Von Mering C., Krause R., Snel, B., Oliver, S.G., Fields, S. and Bork, P
100 Nature 417(2002)399
purified
complexes
Purified TAP
covered by data ( %; log scale)
Complexes (update entire yeast,
Gavin et al., Nature, 2006)
fraction of reference set
HMS-PCI
genomic associations
10 (update to 89 species, 2003)
Coverage
mRNA two methods
synexpression
synthetic
combined
lethality
evidence
1 yeast
two-hybrid three methods
raw data
filtered data
parameter choices
0.1
0.1 1 10 100
Accuracy
fraction of data confirmed by reference set (%; log scale)

5. COX 1 (a target of aspirin)

7. Content
• 373 genomes
• 68,000 chemicals

8. Content
• 11,800 human genes
• 373 genomes • 38,000 chemicals
• 68,000 chemicals • 2100 drugs

10. Interaction types:
e.g. binding, inhibition

12. Phenotypes on a large
scale?

13. Image under CC license, Flickr user: mahalie - “baby eats camera”

15. targets
side effects

16. targets
side effects

17. Side-effect similarity
between drugs
• extract side effects for all drugs
• determine weights for side effects
• compute side-effect similarity for drug pairs
• benchmark: What is the probability that
two drugs share a target?
• DrugBank, Matador, PDSP K Database
i

18. Benchmark

20. Donepezil
Venlafaxine
Pergolide
Rabeprazole
Zolmitriptan
Paroxetine
Fluoxetine

21. Rabeprazole
H
N O
S N
N
O
O
Rabeprazole: proton
pump inhibitor,
used against ulcers

22. Rabeprazole
H
N O
S N
N H
N
NH
O S
H
O
Rabeprazole: proton Pergolide: dopamine
pump inhibitor, receptor agonist, used
used against ulcers for the treatment of
Parkinson’s disease

23. Rabeprazole
H
N O
S N
N H
N
NH
O S
H
O
Rabeprazole: proton Pergolide: dopamine
pump inhibitor, receptor agonist, used
used against ulcers for the treatment of
binds dopamine receptor! Parkinson’s disease

24. Rabeprazole
H
N O
S N
N H
N
NH
O S
H
O
Rabeprazole: proton Pergolide: dopamine
pump inhibitor, receptor agonist, used
used against ulcers for the treatment of
inhibits dopamine receptor!?! Parkinson’s disease

25. 12 of 20 drug pairs
100 1 100 2 100 3 100 4 100 5 100 6
6
Inhibition of control specific binding (%)
50 50 50 50 50 50
0 0 0 0 0 0
8 7 6 5 4 3 8 7 6 5 4 3 8 7 6 5 4 3 8 7 6 5 4 3 8 7 6 5 4 3 8 7 6 5 4 3
100 7 100 8 100 9 100 10 100 11 100 12
50 50 50 50 50 50
0 0 0 0 0 0
8 7 6 5 4 3 8 7 6 5 4 3 8 7 6 5 4 3 8 7 6 5 4 3 8 7 6 5 4 3 8 7 6 5 4 3
-log[drug](M)
9 Ki ≤ 10 μM, 3 Ki > 10 μM

26. Conclusion
• information about drugs makes human
phenotypes accessible
• can infer protein targets from side effects
• next steps: increase resolution, consider
network aspects

27. Acknowledgements
• Peer Bork
• STRING/STITCH: Lars Juhl Jensen,
Christian von Mering and lab
• Side Effect Similarity: Monica Campillos,
Lars Juhl Jensen, Anne-Claude Gavin

28. Thank you for your
attention!
• STRING: http://string.embl.de/
• STITCH: http://stitch.embl.de/
• Matador: http://matador.embl.de/

30. First-level ATC classification
A Alimentary Tract And Metabolism
B Blood And Blood Forming Organs
C Cardiovascular System
D Dermatologicals
G Genito Urinary System And Sex Hormones
H Systemic Hormonal Preparations...
J Antiinfectives For Systemic Use
L Antineoplastic And Immunomodulating Agents
M Musculo-Skeletal System
N Nervous System
P Antiparasitic Products....
R Respiratory System
S Sensory Organs
V Various
Colouring of edges (drug pairs)
known to share targets
with similar structures or targets
without known human targets
from the same therapeutic category
from different therapeutic categories
(unexpected predictions)

31. Donepezil
ACHE
BCHE
Venlafaxine
Pergolide
DRD3
SLC6A4 ATP4B
Rabeprazole
Drug-Target relationships
Zolmitriptan
Paroxetine known main target
other known targets
binding
HTR1D
no binding
Fluoxetine