1. Drug Repurposing Against Infectious
Diseases by Integrating Chemical Genomics
and Structural Systems Biology
Philip E. Bourne1, Lei Xie2
1Skaggs School of Pharmacy and Pharmaceutical Sciences
University of California, San Diego
2Department of Computer Science, Hunter College
Ph.D. Program in Computer Science, Biology, and Biochemistry
The City University of New York
2. Infectious Disease: A Growing Problem
Infectious diseases account for 25% of deaths worldwide
Antimicrobial resistance is increasing
Wide-spread bacteria use antibiotics for nourishment
Clatworthy et al., Nature Chemical Biology, 3(2007), 541 - 548
3. Teaching New Tricks to Old Drugs
Ashburn et al. Nat Rev Drug Disc 3(2004), 673-683
4. Challenges in Drug Repurposing Against
Infectious Diseases
Phenotype-based methods (e.g. gene expression profiles)
- Difficult to compare phenotypes across organisms
- Unknown targets for a large number of bioactive compounds
Ligand-based chemoinformatics methods
- Limited target coverage of pathogen genomes in bioassay databases
- Insufficient models for 3D protein-ligand interactions
Target-based molecular modeling methods (e.g. protein-ligand
docking, MD simulation, structural bioinformatics)
- Not scalable to millions of chemicals and ten thousands of targets
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5. Reconstruction of Genome-Scale
3D Drug-Target Interaction Models
Integrating chemical genomics and structural systems biology
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MD
simulation
Mj
Q
Refined
interaction
model
Mj
Q
geneSAR SMAP
Protein-ligand
docking
Mj
Q
Mi
3D model
of novel
Target
3D model of
annotated
target
Initial
interaction
model
Query
chemical
Network
modeling
Experimental
support
generalized network
enrichment of Structure-
Activity Relationships
7. Generalized Network Enrichment of
Structure-Activity Relationship (geneSAR)
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Bioassay
Database
(ChEMBL,
PubChem etc.)
Ti
Tj
Fingerprint
similarity
Q
Random walk
with restart
(RWR)
Ti
Tj
Ligand
Set
Random
Set
Global
Statistics
Score Distribution
Ti Tj
Q
Ti Tj
8. geneSAR Considerably Improves the
Performance of Drug-Target Interactions
RWR improves both the
sensitivity/specificity and
coverage of chemical similarity
search compared with 2D
fingerprints.
When false positive ratio < 0.05,
geneSAR detects >3 times more
drug-target interactions than SEA.
The success of geneSAR comes
from its combination of RWR and
global statistics.
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9. Detecting Protein Binding Promiscuity
across Fold Space
35% of biologically active compounds bind to two or more targets
that do not have similar sequences or global shapes
Paolini et al. Nat. Biotechnol. 2006 24:805–815
HASSTRVCTVREPRTSEQAENCE
SMAP v2.0
10. Experimental Validation of SMAP
Predictions on Multiple Organisms
Primary Target Off-target Pharmacology
implication
Publication
Human protein
kinase
Bacteria
carboxylase
Drug repurposing for
antibiotics
Miller et al. Proc Natl Acad Sci
USA 106(2009):1737
HIV Protease Human protein
kinase
Drug repurposing for
cancer
Xie et al. PLoS Comp Biol
7(2011):e1002037
Human ER P. auroginosa
PhzB
Drug repurposing for
anti-virulence
Ho Sui et al. Int. J. of
Antimicrobial Agents
40(2012):246-251
T. brucei
RNA-ligase
Human
MECR/ETR1
Serious side effects Durrant et al PLoS Comp Biol
6(2010):e1000648
Human COMT M. tb InhA Drug repurposing for
MDR TB
Kinings et al. PLoS Comp Biol
5(2009):e1000423
http://www.sdsc.edu/pb/ - Drug Discovery Work
11. Case Studies
Repurposing selective estrogen receptor
modulators (SERMs) as anti-virulence agents
Target fishing from the “Malaria Box” and
subsequent drug repurposing
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12. Case Studies
Repurposing selective estrogen receptor
modulators (SERMs) as anti-virulence agents
Target fishing from the “Malaria Box” and
subsequent drug repurposing
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13. Target Species: Pseudomonas
aeruginosa
Opportunistic pathogen causes
infections in individuals with
weak immunity, burn victims, and
patients of cystic fibrosis.
Intrinsic antibiotic resistance
mainly through efflux pump
14. PhzB2 as a Potential Drug Target Interacting with
Selective Estrogen Receptor Modulators
PhzB2 involved in pyocyanin
biosynthesis although its
molecular function remains
unknown
Pyocyanin is both a virulence
factor of bacteria that induce
oxidative stress in host cells
and a quorum sensing signaling
molecule
No human orthologs
Raloxifene (antagonist of ER,
preventive therapy for
osteoporosis) can be docked
into an uncharacterized pocket
PhzB2
15. Experimental Validation
Increased survival rate of infected C. elegans
Reduced virulence factor pyocyanin production
20
30
40
50
60
70
80
90
100
0 39 43 62 67 70 91 95
SurvivalRate(%)
Time (h)
OP50
PAO1
PA01+RAL
PAO1+RAL
PA14
PA14+RAL
(1.6 mg/ml)
(100 mg/ml)
(100 mg/ml)
PA
14
g/m
l)
m
PA
14
+
R
al(12.5
g/m
l)
m
PA
14
+
R
al(25
g/m
l)
m
PA
14
+
R
al(50
g/m
l)
m
PA
14
+
R
al(100
0.0
0.5
1.0
1.5
2.0
2.5
Pyocyanin,mg/mlofculturesupernatant
S.J. Ho Sui, et al. 2012 Int. J. of Antimicrobial Agents (40)3: 246-251
16. Case Studies
Repurposing selective estrogen receptor
modulators (SERMs) as anti-virulence agents
Target fishing from the “Malaria Box” and
subsequent drug repurposing
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17. Malaria
Malaria is a widespread disease, caused by Plasmodium
(P. falciparum and P. vivax)
219 million cases, 1.2 million deaths in 2010
Resistance has developed to anti-malaria drugs.
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18. P. falciparum Drugome
116 drugs, 268 P. falciparum
proteins, and 1120 interactions.
Antimicrobial drugs are most likely to
be anti-malarial drugs
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P fal Drugome: Y. Zhang et al. 2013 Submitted.
TB Drugome: S.L. Kinnings, et al. 2011 PLoS Comp. Biol. 6(11): e1000976
19. Open Access Malaria Box
400 diverse compounds with anti-malaria activity (200 drug-like, 200
probe-like) from whole cell screening of ~4 million of compound.
Molecular targets are unknown.
in vivo anti-malaria activities are unknown
Potential side effects are unknown
The identification of molecular targets in both P. fal and human will:
Optimize these drug-like compounds to be effective therapeutics
Predict potential side effects
Provide insight into potential drug resistance
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20. Targets of Drug-like Compounds from
Chemical Genomics Data (ChEMBL)
157 drug-like compounds are predicted to interact with 427 targets from
multiple organisms using geneSAR (FDR<0.05)
Implication of side effects and drug repurposing for other infectious
diseases
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Target organism phamarcology
Heparanase Human cancer and thrombosis
PDE5A Human Cardiac effect
Dihydroorotate
dehydrogenase
Human inflammation
Sporulation kinase A B. subtilis Gut side effects
hexokinase T. bruci African sleeping sickness
Bontoxilysin-A C. botulinum Neurotoxin
21. Link Approved Drugs with Malaria Box via
Target Interaction Profiling (TIP)
Novel Essential P. fal Target Safe Drug
Dihydroorotate dehydrogenase Leflunomide (anti-inflammation)
Beta-hydroxyacyl-ACP dehydratase Hesperetin ( lowering cholesterol)
Cysteine protease falcipain-3 ?
3-oxoacyl-acyl-carrier protein reductase Desonide (anti-inflammation)
DNA topoisomerase 2 Genistein (cancer prevention)
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genome
Malaria
Box
Drugbank
22. Summary
A new chemical genomics algorithm to identify
drug-target interactions
An integrated chemical genomics and structural
systems biology computational pipeline is able to
generate testable hypotheses for drug
repurposing
This is only the beginning in making a difference
23. Acknowledgement
• Dr. Li Xie (SSPPS, UCSD)
• Mr. Joshua Lerman (Bioengineering, UCSD)
• Ms. Yinliang Zhang (SSPPS, UCSD)
• Ms. Clara Ng (Hunter, CUNY)
• Prof. Fiona Brinkman (Simon Fraser Univ.)
• Dr. Shannan Ho Sui (Harvard University)
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IIS-1242451