Drug Repurposing Against Infectious Diseases
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Drug Repurposing Against Infectious Diseases

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Presented at ISMB Berlin July 23, 2013

Presented at ISMB Berlin July 23, 2013

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    Drug Repurposing Against Infectious Diseases Drug Repurposing Against Infectious Diseases Presentation Transcript

    • 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
    • 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
    • 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 7/22/2013 4
    • Reconstruction of Genome-Scale 3D Drug-Target Interaction Models Integrating chemical genomics and structural systems biology 7/22/2013 5 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
    • Similarity Search Revisit 7/22/2013 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) 7/22/2013 7 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
    • 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. 7/22/2013 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 7/22/2013 11
    • Case Studies  Repurposing selective estrogen receptor modulators (SERMs) as anti-virulence agents  Target fishing from the “Malaria Box” and subsequent drug repurposing 7/22/2013 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 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
    • Case Studies  Repurposing selective estrogen receptor modulators (SERMs) as anti-virulence agents  Target fishing from the “Malaria Box” and subsequent drug repurposing 7/22/2013 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. 7/22/2013 17
    • P. falciparum Drugome  116 drugs, 268 P. falciparum proteins, and 1120 interactions.  Antimicrobial drugs are most likely to be anti-malarial drugs 7/22/2013 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 7/22/2013 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 7/22/2013 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 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) 7/22/2013 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) 7/22/2013 23 IIS-1242451
    • 7/22/2013 24 lei.xie@hunter.cuny.edu pbourne@ucsd.edu http://www.sdsc.edu/pb/ - Drug Discovery Work Funding: NIH