Model Organisms in Drug Discovery

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sirolimus 15 site-specific recombination 106–8 SLI-1 53 SmithKline Beecham 16, 17, 19, 20, 21 sn2 214 snip-SNPs 56 sodium nitroprusside 192, 205 somatic mutation and recombination tests (SMART) 99–100, 101 Sos 125 spe-4 167 specific locus test 230 sphingosine-1-phosphate phosphatase (SPP1) 19, 20 Src42A 171 SREBP pathway 85 Sst2 18 statins 13, 235 Ste5 18 steel 236 structure/activity analysis 20–2 structure/function analysis 20–2 Sucret throat lozenge 25 synaptic vesicle exocytosis 54 synthetic lethality 28, 29 T-cell acute lymphoblastic leukemia 198 tacrine 143 tacrolimus 15 tag arrays 25–6 tail suspension 269 Takeda laboratories 13 TAP 30–1 target discovery 224–5, 227 identification 42, 60–1, 85–92, 127–41, 255–8 validation 42, 45–7, 60–1, 85–92, 127–41, 224–5, 227, 233 targeted gene disruption 138–9 targeted mutagenesis 104–5, 191–2 temperature gradient capillary electrophoresis 233 Tennessee Genome Consortium 237 thapsigargin-resistant SERCA 55 thiazolidinediones 155 thrombocyte aggregation 216 thrombosis 186 thromboxanes 212, 214 tianeptine 92 TILLING 218 tissue-specific growth regulation 271 tissue-specific recessive screens 131–2 Tok1 19 topiramate 92 INDEX 287 topoisomerase inhibitors 14 Tor1 and Tor2 17 Toronto University 237 trace aversive conditioning 270 transgenics Drosophila 108 zebrafish 193–5 transposons 61, 103–4 tricyclic antidepressants 47 triglyceride 263 tropane alkaloids 155 tumor angiogenesis 215 tumor necrosis factor a (TNF-a) 265–6 two-hybrid analysis 30 TXB2 216 tyrosine decarboxylase 94 Uap1 21 UCP1 and UCP3 22 uncoupling protein family 22 Union Biometrica 68 UO126 143 urinalysis 259 valproate 143 Viagra 156 vinblastin 143 voltage-gated ion channels 65–6 warfarin 192, 205 Warner Lambert 21 web sites 31–2, 102, 237 Welbutrin 269 Wg 122–3 WHI1 12 wing spot test 99–100 Wnt-1 122 WNT pathway 84, 120, 122–4, 135 WormBase 56, 57, 60 wortmannin 141, 143 Wyeth 15, 18 X-rays 103, 128, 129, 188 Xenopus laevis 4 XREFdb project 19 yeast 4, 5, 9–39, 158 apoptosis 18–19 biochemical analysis 22, 31 coding regions 11 conservation 12–13 cystic fibrosis 20 databases 24, 31–2 deletion collections 25–9
288 INDEX yeast (continued) function inference 19 G-protein-coupled receptors (GPCRs) 17–18 gene expression profiling 24–5 gene names 11–12 genome 3, 10–13 haploinsufficiency 28 heterologous expression 19–20 homologs 12 immunosuppressive agents 14–17 localization data 31 mass spectrometry 30–1 mechanism elucidation 13–17 mitogen-activated protein kinases (MAPK) 17–18, 21–2 mutant gene mapping 28–9 open reading frame name 11 overexpression analysis 29 pathway deconstruction/reconstruction 18–19 pathway elucidation 13–14, 17–18 phenotypic screens 27 protein function 19–22 proteomics 29–31 reagents and resources 22–3 structure/activity analysis 20–2 structure/function analysis 20–2 synthetic lethality 28, 29 two-hybrid analysis 30 Yeast Proteome Database 24, 32 yeast two-hybrid (Y2H) vectors 59 z 0 -factor 67 zebrafish 4, 6, 185–201, 203–21 conservation 186–7 drug screening 192–3, 210–12 forward genetics 195, 198 genetic screens 187–9, 252 genome 3 genomics 195–7 isotopic labeling 210–11 lipid metabolism screen 206–12 mutagenesis 188–9, 191–2 prostanoid metabolism 212–17 reverse genetics 189–91 targeted mutagenesis 191–2 transgenic 193–5 Zeneca 13 zinc finger nuclease (ZFN) 104–5 ZK222584 192 zonisamide 92 zymosan challenge assay 263
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Model Organisms in Drug Discovery M
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Copyright u 2003 John Wiley & Sons
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Contents List of contributors .....
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CONTENTS ix 7 Genetics and Genomics
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List of Contributors Hector Beltran
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LIST OF CONTRIBUTORS xiii Stefan Sc
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1 Introduction to Model Systems in
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Organism INTEGRATING MODEL ORGANISM
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INTEGRATING MODEL ORGANISM RESEARCH
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INTEGRATING MODEL ORGANISM RESEARCH
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10 GROWING YEAST FOR FUN AND PROFIT
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3 Caenorhabditis elegans Functional
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THE DRUG DISCOVERY PROCESS 43 thoug
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multivulva phenotype of Ras gain-of
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disease. These molecular targets ar
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FROM DISEASE TO TARGET 49 Figure 3.
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FROM DISEASE TO TARGET 51 Figure 3.
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signaling pathway. The third catego
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FROM DISEASE TO TARGET 55 resistant
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phenomenon was first observed in C.
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profiles. The C. elegans gene expre
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emerging technologies. Forward gene
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The compound library LEAD DISCOVERY
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LEAD DISCOVERY 65 previous section,
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LEAD DISCOVERY 67 Figure 3.5 Distri
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Compound learning set for assay val
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10 000-15 000 human drug targets ar
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transporter itself. The SSRIs that
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REFERENCES 75 de Montigny, C., Blie
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REFERENCES 77 Lewis, J. A., Wu, C.
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REFERENCES 79 Tissenbaum, H. A. and
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82 DROSOPHILA AS A TOOL FOR DRUG DI
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100 DROSOPHILA AS A TOOL FOR DRUG D
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5 Drosophila - a Model System for T
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EVOLUTIONARY CONSERVATION OF DISEAS
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TARGET IDENTIFICATION/TARGET VALIDA
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CHEMICAL GENETICS 143 acid identity
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3. A hit identifies a biologically
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about their function in a multicell
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REFERENCES 149 Han, Z. S., Enslen,
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REFERENCES 151 Rintelen, F., Stocke
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6 Mechanism of Action in Model Orga
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INTRODUCTION TO COMPOUND DEVELOPMEN
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MODEL ORGANISMS ARRIVE ON THE SCENE
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ELUCIDATING THE MECHANISM OF COMPOU
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ELUCIDATING THE MECHANISM OF COMPOU
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A CASE STUDY FOR ALZHEIMER’S DISE
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NEW CHEMICAL GENETIC STRATEGIES 171
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A CASE STUDY FOR INNATE IMMUNITY 17
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GLOBAL GENE EXPRESSION STUDIES IN M
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As described above, the extensive i
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REFERENCES 179 Austin, J. and Kimbl
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REFERENCES 181 Hughes, T. R., Marto
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REFERENCES 183 Sin, N., Meng, L., W
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186 GENETICS AND GENOMICS IN THE ZE
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8 Lipid Metabolism and Signaling in
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FISH AS A MODEL ORGANISM 205 genes
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LIPID METABOLISM SCREEN 207 transpo
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LIPID METABOLISM SCREEN 209 Figure
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the embryo media containing radioac
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ZEBRAFISH AS A MODEL SYSTEM 213 Fig
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ZEBRAFISH AS A MODEL SYSTEM 215 Reg
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aspirin, which has potent inhibitor
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REFERENCES 219 Chau, I. and Cunning
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REFERENCES 221 Patrono, C., Patrign
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224 CHEMICAL MUTAGENESIS IN THE MOU
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Page 289 and 290: 284 INDEX L-685,818 16 lead discove
Page 291: 286 INDEX protein function 19-22 pr
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