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Document (b) Chemical structures of representative nonnucleoside inhibitors of HIV-1 RT. Nevirapine: 11 -cyclopropyl-5,11 -dihydro-4-methyl-6H-dipyrido (3,2-b:2'3'-e)(1,4) diazepin-6-one; α-APA: αanilinophenylacetamine; TIBO: tetrahydroimidazo-(4,5,1-jk) (1,4)-benzo-diazepin-2(1H)-one and thione; pyridinones; HEPT: 1-{(2-hydroxyethoxy) methyl}-6-(phenylthio)thymine; BHAP: bis(heteroaryl)piperazine; TSAO: {2',5'-bis-O-(tert-butyldimethylsilyl)}-3' -spiro-5''-(4''-amino-1",2"-oxathiole)-2", 2"-dioxide; L-737,126: 5-chloro- 3-(phenylsulfonyl)indole-2-carboxamide; TBA: 1-(2',6'-difluoro-phenyl)-1H,3H-thiozolo -(3,4-a) -benzimidazole; quinoxaline S-2720: 6-chloro-3,3-dimethyl-4-(isopropenyloxycarbonyl) -3-4-dihydroquinoxalin-2(1H)-thione. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_43.html (1 of 2) [4/5/2004 4:47:21 PM] Page 43
Document dine (3TC), and 2',3'-didehydro-2',3'-dideoxythymidine (d4T), have been widely used in the treatment of HIV-1 infections [5–7]. However, the effectiveness of these drugs is limited <strong>by</strong> their cytotoxicity and the rapid emergence of drug-resistant viral strains [5,8–12]. Nonnucleoside inhibitors, e.g., the HEPT derivatives [13], TIBO derivatives [14], nevirapine [15], pyridinones [16], BHAP derivatives [17], TBA derivatives [18,19], TSAO derivatives [20], α-APA [21], and quinoxalines (HBY) [22,23], are potent inhibitors of HIV-1 RT (see reviews [5,11,12]). While these inhibitors differ considerably in chemical structure, all of them are quite specific for HIV-1 RT and inhibit neither HIV-2 RT nor variety of cellular polymerases. Challenging a virus with these drugs http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_43.html (2 of 2) [4/5/2004 4:47:21 PM]
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netLibrary - eBook Summary Universi
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Page 11 and 12: Document TF—transframe, PR—prot
Page 13 and 14: Document compounds that utilize sim
Page 15 and 16: Document Page 11 retroviral substra
Page 17 and 18: Document Page 13 of the active-site
Page 19 and 20: Document Page 15 Thiazoles are less
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Page 37 and 38: Document Page 33 sustained in many
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Page 45 and 46: Document 47. Tummino PJ, Ferguson D
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Page 49 and 50: Document 74. Reddy RM, Varney MD, K
Page 51 and 52: Document 2 Structural Studies of HI
Page 53: Document Figure 1 (a) Chemical stru
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Page 59 and 60: Document Figure 2 Ribbon diagrams o
Page 61 and 62: Document Figure 3 Overall structure
Page 63 and 64: Document monophosphate analogs whic
Page 65 and 66: Document Analysis of various HIV-1
Page 67 and 68: Document Page 54 Table 2) [12,54].
Page 69 and 70: Document Page 56 It is also attract
Page 71 and 72: Document Table 3 HIV-1 RT Amino Aci
Page 73 and 74: Document ever, once an NNRTI is bou
Page 75 and 76: Document Page 61 now clear that the
Page 77 and 78: Document Page 63 most of the amino
Page 79 and 80: Document Page 65 cal properties of
Page 81 and 82: Document Page 67 Biochemical data s
Page 83 and 84: Document Page 69 determining the me
Page 85 and 86: Document Chris Tantillo. The work i
Page 87 and 88: Document Page 72 16. Goldman ME, Nu
Page 89 and 90: Document 30. Coffin JM. HIV populat
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Page 93 and 94: Document reverse transcriptase inhi
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Page 97 and 98: Document 89. Hughes SH, Arnold E, H
Page 99 and 100: Document 106. Cirino NM, Cameron CE
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Page 103 and 104: Document dine) and didanosine (dide
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Document 149. Craig JC, Duncan IB,
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Document 163. Lacey SF, Larder BA.
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Document Figure 1 Retroviral lifecy
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Document Figure 2 In vivo reactions
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Document Page 88 transfer (Figure 3
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Document Page 92 The role of the N-
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Document Page 96 region in the HIV-
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Document day junction resolving enz
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Document -62° for HIV-1 integrase,
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Document Page 101 crystallized unde
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Document Figure 8 Molscript stereo
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Document proposed mechanisms. For e
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Document Page 106 on the same ring
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Document Page 108 mulate during tre
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Document when metals are bound. Fin
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Document cubation of phosphotyrosin
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Document 4. Vink C, Plasterk RHA. T
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Document 65. Gallay P, Swingler S,
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Document 4 Bradykinin Receptor Anta
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Document Page 121 Nearly all cells
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Document Page 123 were poorly satis
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Document Page 125 binding site on t
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Document Page 127 The des-Arg 9 for
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Document Page 129 tolerated by the
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Document receptor, it has not yet b
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Document Page 133 This initial stag
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Document Page 135 might be jointly
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Document Page 137 observed for the
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Document Figure 6 Rat and human B2
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Document Page 141 receptor with int
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Document Figure 9 Composition of te
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Document 16. Martorana PA, Kettenba
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Document 39. Mavunkel BJ, Lu Z, Kyl
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Document B. Pharmacology Figure 1 T
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Document We determined the structur
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Document Figure 3 Previously known
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Document large solvent channels and
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Document IV. Drug Design Progressio
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Document position eight from formin
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Document Table 1 Inhibition Data fo
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Document Page 166 As predicated, th
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Document References 1. Parks RE Jr.
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Document 17. Ealick SE, Rule SA, Ca
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Document 6 Structural Implications
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Document Figure 1 A ribbon model of
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Document Page 176 0.43 Å) as the c
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Document Page 182 (SAR) model. The
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Document 7 Structure—Function Rel
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Document Figure 1 Reactions catalyz
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Document Figure 2 Structure of lico
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Document Figure 3 (Continued) Page
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Document Important for the validity
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Document Figure 4 Amino acids impor
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Document III. Results and Discussio
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Document Page 202 269, and valine-2
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Document Figure 6 Structure of α h
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Document Page 205 enzyme and of phe
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Document Page 207 sure and the acti
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Document 13. Wilson RC, Krozowski Z
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Document 29. Baker ME. Genealogy of
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Document Page 214 viruses. Specific
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Document Figure 3 (a) Ternary compl
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Document Figure 5 (a) Staurosporine
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Document protein kinase core is ess
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Document 10. Knighton DR, Zheng J-H
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Document 24. Madhusudan Xuong N-H,
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Document 9 Structural Studies of Al
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Document diverse ARIs have been sho
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Document Figure 3 C α trace of the
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Document Figure 4 Surface represent
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Document Figure 5 Schematic represe
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Document Figure 7 Stereo of zopolre
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Document B. Structures Figure 8 Seq
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Document This method was used to sc
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Document 35. Pailhoux EA, Martinez
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Document 10 Structure-Based Design
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Document Cyclotheonamide A (CtA), a
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Document Page 256 The discovery pro
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Document et al. [21]). Among these
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Document balance its pro- and antic
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Document Page 263 15. Tabernero L,
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Document 31. Kettner C, Shaw E. D-P
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Document Figure 1 The coagulation c
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Document Figure 2 Factor Xa structu
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Document Table 2 Naturally Occurrin
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Document Table 3 Active Site Sequen
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Document Figure 5 Predicted seconda
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Document Lys in the P1 position is
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Document Page 276 In both cases the
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Document Figure 10 Proposed model o
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Document Figure 11 dArg-ATS 32-38 m
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Document 12 Polypeptide Modulators
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Document Page 297 whereas, calcium
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Document Figure 2 Amino acid sequen
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Document A. Chemical Modification P
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Document 13 Rational Design of Reni
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Document Page 323 been suggested th
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Document Page 327 this analog inter
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Document plasma. This may arise fro
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Document C. Specificity Figure 4 Th
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Document Figure 5 The S 3 specifici
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Document IV. Rational Drug Design F
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Document 2. Blundell TL, Cooper J,
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Document 17. Szelke M. Chemistry of
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Document 34. Rosenberg SH, Plattner
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Document Page 343 14 Structural Asp
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Document Figure 2 The reaction cata
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Document Figure 4 Amino acid sequen
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Document Figure 5 Schematic stereo
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Document Figure 8 The catalytic mac
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Document Figure 10 Structures of so
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Document From quantitative structur
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Document Page 355 with the tryptoph
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Document Figure 14 The energy profi
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Document Page 359 easily reach the
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Document 35. Davis TL, Roznoski M,
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Document Figure 1 Available drugs f
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Document Table 1 Trypanosomal Targe
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Document Table 2 Three-Dimensional
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Document Figure 2 Glycolysis in blo
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Document II. Three Glycolytic Enzym
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Document Figure 4 Stereoview of sup
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Document Figure 6 Stereoview of NAD
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Document Because there are tens of
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Document 5-Methoxytryptamine 19.0 9
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Document Figure 11 Two-dimensional
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Document Figure 12 Predicted bindin
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Document Page 388 nosine proved to
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Document 16 Progress in the Design
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Document Table 1 Known Three-Dimens
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Document Page 398 with growth hormo
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Document All effects of the IL-1 fa
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Document has a single membrane-span
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Document Figure 2 Structural alignm
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Document Page 405 strands constitut
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Document Figure 4 (a) Stereo diagra
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Document Figure 6 (a) Stereo diagra
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Document Figure 7 (a) Superposition
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Document Page 412 ture is unlike ot
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Document Figure 10 Schematic diagra
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Document Page 416 positions of the
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Document Figure 11 Functional resid
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Document Figure 13 The identified p
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Document B. Interleukin-1 Receptor
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Document Page 423 American Home Pro
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Document Page 425 Antinflammatory D
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Document Page 427 These aromatic di
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Document 5. Dinarello CA. On the Bi
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Document 21. Seckinger P, Lowenthal
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Document 39. Saurat JH, Schfferli J
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Document receptor antagonist into a
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Document 74. Bender PE, Lee JC., ed
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Document 102. Machin PJ, Osbond JM,
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Document 17 Structure and Functiona
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Document Table 1 Approval Indicatio
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Document Page 438 proteins. One pot
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Document II. Type IFNs A great deal
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Document Page 441 sequence of the m
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Document Page 443 that allowed for
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Document Figure 4 Stereo view of IF
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Document Figure 5 Velcro-key model
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Document Figure 6 Proposed receptor
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Document Page 451 with the cytoplas
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Document for directed subcellular t
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Document Figure 1 A schematic diagr
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Document Page 462 strains of influe
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Document Page 464 could not again b
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Document Figure 3 (a) A MOLSCRIPT [
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Document B. Protein Structure Page
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Document Figure 5 (a) Stereo image
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Document Page 471 molecules in the
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Document hydroxy, and 6 Neu5Ac2en -
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Document Figure 8 Stereo image of t
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Document Page 476 nM, respectively.
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Document Page 478 lished—was asso
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Document VI. Conclusion Page 480 It
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Document Page 488 against most of t
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Document A. The Canyon Page 491 The
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Document Subsequent studies have sh
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Document Page 495 of the RNA and pr
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Document Figure 4 A ribbon diagram
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Document Figure 5 Some compounds wh
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Document Figure 7 HRV14 VP1 hydroph
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Document C. Structure-Activity Rela
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Document Figure 9 A solvent-accessi
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Document accommodate a variety of d
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Document Figure 10 Possible hydroge
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Document Page 514 sis. Large number
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Document conformational transition
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Document Page 518 The differences b
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Document Figure 3 Generation of com
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Document ciency of drug discovery (
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Document Figure 32 PTP and PTB 3D s
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Document Acknowledgments Page 620 I
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Document Med Biol 1991; 306:9-21; (
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Document Page 629 ML, Clare M, Decr
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Document site, 52, 55, 61 triad, 24
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Document factors, 247 Combination t
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Document Cyclotheonamide A (CtA), 2
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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Document fragment-based programs, 5
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Document [Human immunodeficiency vi
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Document antagonistic activity, 416
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Document [Interleukin-1] homology w
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Document Kininogen, 119 high molecu
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Document Matrix-metalloproteinase (
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Document RT inhibitor, 41, 56 Nonpe
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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