From protein interaction networks to human phenotypes

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

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From protein interaction networks to human phenotypes

  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)
  4. COX 1 (a target of aspirin)
  5. Content • 373 genomes • 68,000 chemicals
  6. Content • 11,800 human genes • 373 genomes • 38,000 chemicals • 68,000 chemicals • 2100 drugs
  7. Interaction types: e.g. binding, inhibition
  8. Phenotypes on a large scale?
  9. Image under CC license, Flickr user: mahalie - “baby eats camera”
  10. targets side effects
  11. targets side effects
  12. 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
  13. Benchmark
  14. Donepezil Venlafaxine Pergolide Rabeprazole Zolmitriptan Paroxetine Fluoxetine
  15. Rabeprazole H N O S N N O O Rabeprazole: proton pump inhibitor, used against ulcers
  16. 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
  17. 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
  18. 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
  19. 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
  20. Conclusion • information about drugs makes human phenotypes accessible • can infer protein targets from side effects • next steps: increase resolution, consider network aspects
  21. Acknowledgements • Peer Bork • STRING/STITCH: Lars Juhl Jensen, Christian von Mering and lab • Side Effect Similarity: Monica Campillos, Lars Juhl Jensen, Anne-Claude Gavin
  22. Thank you for your attention! • STRING: http://string.embl.de/ • STITCH: http://stitch.embl.de/ • Matador: http://matador.embl.de/
  23. 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)
  24. 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

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