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Computational Biology Signaling networks and drug repositioning Lars Juhl Jensen
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sequence analysis
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Jensen, Gupta et al., Journal of Molecular Biology, 2002
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data integration
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de Lichtenberg, Jensen et al., Science, 2005
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text mining
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Pafilis, O’Donoghue, Jensen et al., Nature Biotechnology, 2009
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human variation
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signaling networks
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phosphoproteomics
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in vivo phosphosites
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kinases are unknown
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sequence motifs
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Miller, Jensen et al., Science Signaling, 2008
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NetPhorest
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data organization
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Miller, Jensen et al., Science Signaling, 2008
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automated pipeline
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Miller, Jensen et al., Science Signaling, 2008
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compilation of datasets
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training and evaluation
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motif atlas
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179 kinases
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89 SH2 domains
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8 PTB domains
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BRCT domains
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WW domains
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14-3-3 proteins
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sequence specificity
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kinase-specific
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in vitro
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network context
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Linding, Jensen, Ostheimer et al., Cell, 2007
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STRING
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Jensen, Kuhn et al., Nucleic Acids Research, 2009
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630 genomes
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2.5 million proteins
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genomic context
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gene fusion
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Korbel et al., Nature Biotechnology, 2004
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phylogenetic profiles
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Korbel et al., Nature Biotechnology, 2004
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primary experimental data
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physical interactions
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Jensen & Bork, Science, 2008
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gene coexpression
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curated knowledge
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Letunic & Bork, Trends in Biochemical Sciences, 2008
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literature mining
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not comparable
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confidence scores
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von Mering et al., Nucleic Acids Research, 2005
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cross-species integration
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Linding, Jensen, Ostheimer et al., Cell, 2007
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putting it all together
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NetworKIN
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Linding, Jensen, Ostheimer et al., Cell, 2007
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>2x better accuracy
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use case
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DNA damage response
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Linding, Jensen, Ostheimer et al., Cell, 2007
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experimental validation
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ATM phosphorylates Rad50
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Linding, Jensen, Ostheimer et al., Cell, 2007
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drug repositioning
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new uses for old drugs
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drug–drug network
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shared target(s)
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chemical similarity
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Tanimoto coefficients
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Campillos & Kuhn et al., Science, 2008
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similar drugs share targets
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only trivial predictions
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phenotypic similarity
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chemical perturbations
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phenotypic readouts
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drug treatment
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side effects
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no database
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package inserts
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Campillos & Kuhn et al., Science, 2008
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text mining
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side-effect ontology
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backtracking
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Campillos & Kuhn et al., Science, 2008
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side-effect correlations
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Campillos & Kuhn et al., Science, 2008
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GSC weighting
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side-effect frequencies
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Campillos & Kuhn et al., Science, 2008
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raw similarity score
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Campillos & Kuhn et al., Science, 2008
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p-values
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Campillos & Kuhn et al., Science, 2008
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side-effect similarity
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chemical similarity
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Campillos & Kuhn et al., Science, 2008
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confidence scores
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drug–drug network
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Campillos & Kuhn et al., Science, 2008
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categorization
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Campillos & Kuhn et al., Science, 2008
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experimental validation
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20 drug–drug relations
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in vitro binding assays
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K i <10 µM for 11 of 20
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cell assays
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9 of 9 showed activity
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summary
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computational biology
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network analysis
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testable predictions
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save much time in the lab
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Acknowledgments NetPhorest.info –Rune Linding –Martin Lee Miller –Francesca Diella –Claus Jørgensen –Michele Tinti –Lei Li –Marilyn Hsiung –Sirlester A. Parker –Jennifer Bordeaux –Thomas Sicheritz-Pontén –Marina Olhovsky –Adrian Pasculescu –Jes Alexander –Stefan Knapp –Nikolaj Blom –Peer Bork –Shawn Li –Gianni Cesareni –Tony Pawson –Benjamin E. Turk –Michael B. Yaffe –Søren Brunak STRING-DB.org –Christian von Mering –Damian Szklarczyk –Michael Kuhn –Manuel Stark –Samuel Chaffron –Chris Creevey –Jean Muller –Tobias Doerks –Philippe Julien –Alexander Roth –Milan Simonovic –Jan Korbel –Berend Snel –Martijn Huynen –Peer Bork Side effect –Monica Campillos –Michael Kuhn –Christian von Mering –Anne-Claude Gavin –Peer Bork NetworKIN.info –Rune Linding –Gerard Ostheimer –Heiko Horn –Martin Lee Miller –Francesca Diella –Karen Colwill –Jing Jin –Pavel Metalnikov –Vivian Nguyen –Adrian Pasculescu –Jin Gyoon Park –Leona D. Samson –Rob Russell –Peer Bork –Michael Yaffe –Tony Pawson
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