Networks of Drugs &

Drug Targets
Muhammed Ali Yldrm
Vidal & Barabsi Labs
Harvard University
Dana Farber Cancer Institute
NetSci Meeting May 23
rd
, 2007 New York
Imatinib (Gleevec)
BCR-ABL
c-KIT PDGFRa
Chronic Myelogenous Leukaemia
Gastrointestinal Stromal Tumor
Reduces
Inflammation
Fever
Pain

Reduces the risk of
breast cancer
ovarian cancers
colorectal cancer
COX2
30 other inhibitors
Direct relation
with diseases
Indirect relation
with diseases
Motivation
How do drug targets relate to disease-causing
genes?
NETWORK BIOLOGY
Different drug targets have distinctive relations to
disease genes, i.e. different mechanisms
Many drugs target more than one protein
For many targets, there are more than one drug
What is intentional and what is accidental?
What have been the trends in the drug industry?
DRUGS
TARGET
PROTEINS
DTN

Wishart DS et al., Nucleic Acids Res. 2006 1;34
http://redpoll.pharmacy.ualberta.ca/drugbank/
DRUGBANK Database
1179 FDA-approved small molecule &
biotech drugs (different chemical entities)
890 / 1179 has human protein targets
390 Human Drug Target Proteins for
Approved Drugs.
Drug Target Network
Randomized: 1090 17
Observed: 588
A global measure of local clustering.
Topological features
Giant component size
Trends in Industry
Majority of the new drugs target already targeted
proteins (me too drugs) - slow rate of target innovation.
We can probe the new trends of drug development by looking
at changes in the Drug Target Network with addition of
Experimental drugs.
3200 Experimental drugs

1014 Human Drug target Proteins with addition of
Experimental Drugs.
Topological Changes: Giant Component Size
Randomized: 2213 25
Observed: 2001
All FDA Approved
Randomized: 1034 22
Observed: 1197
Experimental
Experimental drugs are more diverse, and promiscuity of
the drugs are closer to random.
Randomized: 1090 17
Observed: 588
Target Proteins (TP)
Experimental Targets
TP Last 10 years
Cellular Location Profiles
Disease Proteins
Motivation
What have been the trends in the drug industry?
- Mostly me too drugs
- But becoming more diverse
How do drug targets relate to disease-causing
genes?
DISEASE
PHENOME
DISEASE
GENOME
DISEASOME

Total number of diseases
1,286
Total number of disease
genes 1,777
Goh, K.I. et al, PNAS 2007
Diseasome
Disease
Genes
Disorders
Disorders
Disease
Genes
Approved
Targets
Experimental
Targets
Drug Targets in Diseasome
Drug Targets
1
st
Neighbors: 2
nd
Neighbors: 3
rd
Neighbors:
3
1
5
2
6
1
Drug Targets in Diseasome
Fractions of Drug Targets
0
0.1
0.2
0.3
1 2 3 4 5
Distance
F
r
a
c
t
i
o
n
Targets
All
Drug Targets in Diseasome
0.1
0.2
0.3
1 2 3 4 5
Distance
F
r
a
c
t
i
o
n
Approved Targets
in the Diseasome
All Targets in the
Diseasome
Lindpaintner, K. Nat. Rev. Drug Disc. 1, 463-469 (2002)
Drug Targets and Disease Genes
Many drugs do not target
disease-causing genes
Protein-protein interaction information to quantify
the relations of drug targets to disease genes
PPI Network
PPI data from Rual et al (2005) + Stelzl et al (2005) +
Literature curated interactions
Quantifying Relations of Drug Targets and Disease Genes
Disease
Genes
Drug Targets
Protein-Protein Interactions
The particular drug is indicated for the disease
Random control: Keep disease genes constant, randomly select same
number of drug targets
Drug targets vs Disease Genes on the PPI Network
0
0.1
0.2
0.3
0.4
0.5
0 1 2 3 4 5 6 7 8 9 10
Distance
F
r
a
c
t
i
o
n
Drug Targets vs Disease Genes
Random
Drug targets vs Disease Genes on the PPI Network
0
0.1
0.2
0.3
0.4
0 1 2 3 4 5 6 7 8 9 10
Distance
F
r
a
c
t
i
o
n
Pre 1996
Post 1996
Average Distance for Different Disease Categories
0
0.5
1
1.5
2
2.5
3
3.5
4
Cancer Respiratory Psychiatric Endocrine
Disease Class
A
v
e
r
a
g
e

S
h
o
r
t
e
s
t

D
i
s
t
a
n
c
e
Disease Genes vs Drug Targets
Random Control
0
10
20
30
40
0 1 2 3 4 5
Distance
#

o
f

D
r
u
g

-

C
a
n
c
e
r

P
a
i
r
s
Cancer Drugs vs Cancer Genes
Imatinib Gastrointestinal stromal tumor
Imatinib Leukemia
Abarelix Prostate cancer
Carmustine Non-Hodgkin lymphoma
Leuprolide Prostate cancer
Zoledronate Multiple myeloma
Conclusions
Abundance of me too drugs

Evolution towards more diverse set of
targets

Targeting clustered regions in the Human
Disease Network

Drugs mostly act palliatively

Acknowledgements
CCSB / Vidal / Barabasi labs
Kwang-Il Goh
Michael Cusick
Albert-Lszl Barabsi
Marc Vidal