network medicine - integrating drugs, targets, diseases and side-effects

Lars Juhl Jensen

Network medicineIntegrating drugs, targets, diseases and side-effects

Lars Juhl Jensen

Network medicineIntegrating drugs, targets, diseases and side-effects

Lars Juhl Jensen

Network medicineIntegrating drugs, targets, diseases and side-effects

what went wrong?

phase 0

before you do anything

a good problem

a good idea

dynamics of complexes

microarray data

protein interactions

de Lichtenberg, Jensen, et al., Science, 2005

phosphorylation networks

mass spectrometry data

sequence motifs

functional associations

Linding, Jensen, Ostheimer et al., Cell, 2007

Linding, Jensen, Ostheimer et al., Cell, 2007

the problem

new uses for old drugs

drug–drug network

shared target(s)

chemical similarity

Tanimoto coefficients

similar drugs share targets

only trivial predictions

the idea

chemical perturbations

phenotypic readouts

drug treatment

side effects

the implementation

information on side effects

package inserts

text mining

side-effect ontology

backtracking

side-effect correlations

GSC weighting

side-effect frequencies

raw similarity score

p-values

side-effect similarity

chemical similarity

reference set

drug–target pairs

drug–drug pairs

score bins

benchmark

fit calibration function

probabilistic scores

the results

drug–drug network

ATC codes

categorization

map onto score space

the experiments

20 drug–drug relations

in vitro binding assays

Ki<10 µM for 11 of 20

cell assays

9 of 9 showed activity

the big picture

STITCH

protein–chemical network

primary experimental data

activity screens

Fedorov et al., PNAS, 2007

protein interactions

Jensen & Bork, Science, 2008

gene coexpression

genomic context

Korbel et al., Nature Biotechnology, 2004

literature mining

curated knowledge

Letunic & Bork, Trends in Biochemical Sciences, 2008

different formats

different identifiers

different reliability

benchmarking

von Mering et al., Nucleic Acids Research, 2005

373 genomes

Jensen et al., Nucleic Acids Research, 2008

transfer by orthology

combine all evidence

Acknowledgments

Monica Campillos

Michael Kuhn

Christian von Mering

Anne-Claude Gavin

Peer Bork

http://larsjuhljensen.wordpress.com