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Presented at ISMB Berlin July 23, 2013
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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 Diego2Department of Computer Science, Hunter College
Ph.D. Program in Computer Science, Biology, and Biochemistry
The City University of New York
Infectious Disease: A Growing Problem
Infectious diseases account for 25% of deaths worldwide Antimicrobial resistance is increasing
Wide-spread bacteria use antibiotics for nourishmentClatworthy et al., Nature Chemical Biology, 3(2007), 541 - 548
Teaching New Tricks to Old Drugs
Ashburn et al. Nat Rev Drug Disc 3(2004), 673-683
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
04/11/2023 4
Reconstruction of Genome-Scale 3D Drug-Target Interaction Models
Integrating chemical genomics and structural systems biology
04/11/2023 5
MDsimulation
Mj
Q
Refinedinteractionmodel
MjQ
geneSAR SMAP
Protein-liganddocking
Mj
Q
Mi
3D model of novelTarget
3D model ofannotated target
Initialinteractionmodel
Querychemical
Networkmodeling
Experimentalsupport
generalized networkenrichment of Structure-Activity Relationships
Similarity Search Revisit
04/11/2023 6
1
1
0 1
0
0
Query
False Negative
False Positive
Query
2.8
2.8
2.2 1.7
1.2
1.2
Generalized Network Enrichment of Structure-Activity Relationship (geneSAR)
04/11/2023 7
BioassayDatabase
(ChEMBL, PubChem etc.)
TiTj
Fingerprintsimilarity
Q
Random walk with restart(RWR)
TiTj
LigandSet
RandomSet
GlobalStatistics
Score Distribution
Ti Tj
Q
Ti Tj
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.
04/11/2023 8
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
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
Case Studies
Repurposing selective estrogen receptor modulators (SERMs) as anti-virulence agents
Target fishing from the “Malaria Box” and subsequent drug repurposing
04/11/2023 11
Case Studies
Repurposing selective estrogen receptor modulators (SERMs) as anti-virulence agents
Target fishing from the “Malaria Box” and subsequent drug repurposing
04/11/2023 12
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
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
Experimental Validation
Increased survival rate of infected C. elegans Reduced virulence factor pyocyanin production
0 39 43 62 67 70 91 9520
30
40
50
60
70
80
90
100
OP50PAO1PA01+RALPAO1+RALPA14PA14+RAL
Time (h)
Su
rviv
al R
ate
(%
)
(1.6 mg/ml)(100 mg/ml)
(100 mg/ml)PA14
g/ml)
PA14
+ R
al (1
2.5
g/ml)
PA14
+ R
al (2
5 g/m
l)
PA14
+ R
al (5
0 g/m
l)
PA14 +
Ral
(100
0.0
0.5
1.0
1.5
2.0
2.5
Pyo
cyan
in,
g/m
l of
cult
ure
su
per
nat
ant
S.J. Ho Sui, et al. 2012 Int. J. of Antimicrobial Agents (40)3: 246-251
Case Studies
Repurposing selective estrogen receptor modulators (SERMs) as anti-virulence agents
Target fishing from the “Malaria Box” and subsequent drug repurposing
04/11/2023 16
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.
04/11/2023 17
P. falciparum Drugome
116 drugs, 268 P. falciparum proteins, and 1120 interactions.
Antimicrobial drugs are most likely to be anti-malarial drugs
04/11/2023 18
P fal Drugome: Y. Zhang et al. 2013 Submitted.TB Drugome: S.L. Kinnings, et al. 2011 PLoS Comp. Biol. 6(11): e1000976
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
04/11/2023 19
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
04/11/2023 20
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
Link Approved Drugs with Malaria Box viaTarget 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)
04/11/2023 21
genome
Malaria Box
Drugbank
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
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)
04/11/2023 23
IIS-1242451
04/11/2023 24
Thank You
http://www.sdsc.edu/pb/ - Drug Discovery Work
Funding: NIH