From Chemoinformatics to Systems Chemical Biology Irene Kouskoumvekaki, Associate Professor, Computational Chemical Biology, CBS, DTU-Systems Biology #27803, Biological Sequence Analysis, May 6, 2011

2CBS, Department of Systems Biology The Systems Era

3CBS, Department of Systems Biology Clinical effect of drug compounds Therapeutic outcome Slide adapted from Francisco Roque’s PhD thesis

4CBS, Department of Systems Biology Clinical effect of drug compounds Side Effects Therapeutic outcome Slide adapted from Francisco Roque’s PhD thesis

5CBS, Department of Systems Biology Drug selectivity towards a single target is more often the exception than the rule Many effective drugs act via modulation of multiple targets Some drugs may have yet unknown therapeutic applications(drug repurposing) Many adverse drug reactions are due to activity towards multiple targets Clinical effect of drug compounds

6CBS, Department of Systems Biology Drug repurposing Sildenafil (a.k.a Viagra, Vitamin V, the Blue Pill, etc) –Potent inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5), an enzyme that regulates blood flow –Initially developed to treat pulmonary hypertension (market name: Revatio) –Sales account for 90% of the global market for erectile dysfunction –Recently discovered uses include alleviation of altitude sickness and jetlag

7CBS, Department of Systems Biology Adverse Drug Reactions Cisapride: serotonin receptor agonist –Relief of gastrointestinal symptoms Astemizole: histamin receptor antagonist –Antihistamine BOTH WITHDRAWN DUE TO INHIBITION OF THE hERG CARDIAC ION CHANNEL

8CBS, Department of Systems Biology Adverse Drug Reactions Many different studies demonstrate a link between depression, schizophrenia and diabetes. But what is the link? Suspicions that antipsychotic drugs interfere with pathways involved to insulin resistance

9CBS, Department of Systems Biology Oprea et al. Nature Chem Biol (2007) 3, Small compounds Structural information Bioactivity information Human body Biological pathways Protein-protein interactions Gene expression data Disease phenotypes Side effect data, etc... POLYPHARMACOLOGY CHEMOGENOMICS NETWORK PHARMACOLOGY SYSTEMS PHARMACOLOGY

10CBS, Department of Systems Biology Systems Chemical Biology Butcher EC, Berg EL, Kunkel EJ. Systems biology in drug discovery. Nat Biotech 2004; 22:

11CBS, Department of Systems Biology T. Oprea et al, Computational Systems Chemical Biology, Chemoinformatics and Computational Chemical Biology, Ed J. Bajorath, Springer, 2011

12CBS, Department of Systems Biology Network visualization Chen et al., BMC Bioinformatics, 2010, 11:255

13CBS, Department of Systems Biology Network visualization Bipartite network Unipartite networks Montanez et al., BioEssays, 2010, 32:

14CBS, Department of Systems Biology Drug-Disease Network (bipartite) drugs diseases FDA approved drugs ATC codes Drug-Disease Network Disease names

15CBS, Department of Systems Biology Drug-Drug Network (unipartite) Ocular hypertension

16CBS, Department of Systems Biology Disease-Disease Network (unipartite)

17CBS, Department of Systems Biology S. Berger and R. Iyengar, Bioinformatics, 2009, 25(19), new druggable targets drug repurposing side effects, toxicity

18CBS, Department of Systems Biology Case Study Dasatinib: tyrosine kinase inhibitor treatment of chronic mylogenous leukemia

19CBS, Department of Systems Biology S. Berger and R. Iyengar, Bioinformatics, 2009, 25(19),

20CBS, Department of Systems Biology S. Berger and R. Iyengar, Bioinformatics, 2009, 25(19),

21CBS, Department of Systems Biology S. Berger and R. Iyengar, Bioinformatics, 2009, 25(19), anti-neoplastic anti-inflammatory topical acne

22CBS, Department of Systems Biology Chemical-biological triplets (drug-target-pathway) Chen et al., BMC Bioinformatics, 2010, 11:255

23CBS, Department of Systems Biology Drug-Target Network (known) MJ Keiser et al. Nature, 2009, 12(462),

24CBS, Department of Systems Biology Drug-Target Network (predicted) MJ Keiser et al. Nature, 2009, 12(462),

25CBS, Department of Systems Biology Discovered off-targets network MJ Keiser et al. Nature, 2009, 12(462),

26CBS, Department of Systems Biology Summarizing…  Network approaches allow researchers to rapidly organize and extrapolate available knowledge by integrating different types of large datasets.  Application of such methods in drug research allow:  Systems level description of drug action  Explanation of side effects  Drug repurposing  Identification of novel drug targets and therapeutic strategies  Prediction of effective drug combinations  Better understanding of complex diseases

27CBS, Department of Systems Biology Questions?