From Chemoinformatics to
Systems Chemical Biology
Irene Kouskoumvekaki,
Associate Professor,
Computational Chemical Biology,
CBS, DTU-Systems Biology
#27803, Biological Sequence Analysis, May 6, 2011
The Systems Era
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CBS, Department of Systems Biology
Clinical effect of drug compounds
Therapeutic outcome
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CBS, Department of Systems Biology
Slide adapted from Francisco Roque’s PhD thesis
Clinical effect of drug compounds
Side Effects
Therapeutic outcome
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CBS, Department of Systems Biology
Slide adapted from Francisco Roque’s PhD thesis
Clinical effect of drug compounds
• 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
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CBS, 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
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CBS, 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BOTH WITHDRAWN DUE TO INHIBITION OF THE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
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CBS, 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
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CBS, Department of Systems Biology
Oprea et al. Nature Chem Biol (2007) 3, 447-450
POLYPHARMACOLOGY
CHEMOGENOMICS
Human body
NETWORK
PHARMACOLOGY
SYSTEMS
Small compounds
Biological pathways
PHARMACOLOGY
Structural information
Protein-protein interactions
Bioactivity information
Gene expression data
Disease phenotypes
Side effect data,
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CBS, Department of Systems Biology
etc... etc...
Systems Chemical Biology
Butcher EC, Berg EL, Kunkel EJ. Systems biology in drug discovery. Nat Biotech 2004; 22: 1253-9.
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CBS, Department of Systems Biology
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CBS, Department of Systems Biology
T. Oprea et al, Computational Systems Chemical Biology, Chemoinformatics and
Computational Chemical Biology, Ed J. Bajorath, Springer, 2011
Network visualization
Chen et al., BMC Bioinformatics, 2010, 11:255
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CBS, Department of Systems Biology
Network visualization
Bipartite network
Unipartite networks
Montanez et al., BioEssays, 2010, 32:246-256
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CBS, Department of Systems Biology
Drug-Disease Network (bipartite)
FDA approved drugs
Disease names
ATC codes
Drug-Disease Network
drugs
diseases
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CBS, Department of Systems Biology
Drug-Drug Network (unipartite)
Ocular
hypertension
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CBS, Department of Systems Biology
Disease-Disease Network (unipartite)
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CBS, Department of Systems Biology
• new druggable
targets
• drug
repurposing
• side effects,
toxicity
S. Berger and R. Iyengar, Bioinformatics, 2009, 25(19), 2466-72
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CBS, Department of Systems Biology
Case Study
Dasatinib:
• tyrosine kinase inhibitor
• treatment of chronic mylogenous leukemia
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CBS, Department of Systems Biology
S. Berger and R. Iyengar, Bioinformatics, 2009, 25(19), 2466-72
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CBS, Department of Systems Biology
S. Berger and R. Iyengar, Bioinformatics, 2009, 25(19), 2466-72
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CBS, Department of Systems Biology
topical acne
anti-neoplastic
anti-inflammatory
S. Berger and R. Iyengar, Bioinformatics, 2009, 25(19), 2466-72
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CBS, Department of Systems Biology
Chemical-biological triplets
(drug-target-pathway)
Chen et al., BMC Bioinformatics, 2010, 11:255
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CBS, Department of Systems Biology
Drug-Target Network (known)
MJ Keiser et al. Nature, 2009, 12(462), 175-81
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CBS, Department of Systems Biology
Drug-Target Network (predicted)
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CBS, Department of Systems Biology
MJ Keiser et al. Nature, 2009, 12(462), 175-81
Discovered off-targets network
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CBS, Department of Systems Biology
MJ Keiser et al. Nature, 2009, 12(462), 175-81
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
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Better understanding of complex
diseases
CBS, Department of Systems Biology
Questions?
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CBS, Department of Systems Biology