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Document Figure 6 Change of the binding mode of compound III observed during iterative design of AG1284. (a) Crystallographically determined binding mode of compound II. Pseudosymmetrically distributed aryl groups are bound in the S1 and S1' specificity subsites. (b) Crystallographically determined binding mode of compound III. Note the inversion of the binding mode. The ortho-substituted benzyl groups bind in a pseudosymmetric fashion in the S2 and S2' subsites. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_26.html (1 of 2) [4/5/2004 4:46:26 PM] Page 26
Document Page 27 volume of the active site. With this in mind, the dimethylbenzyl group was attached to compound III and the additional phenyl ring was accommodated well in the lipophilic pocket of the S1'/S3' sides. As the S1 pocket was not fully occupied, a Monte Carlo-based De Novo Ligand-Generating program (MCDNLG) [46] was used to identify other amide substituents that might fill this subsite more effectively. From several moieties identified by the MCDNLG program, a larger cyclopentylethyl group showing very good shape complementarity to the S1/S3 subsite was selected for synthesis. In addition, due to the asymmetrical nature of this compound, additional space was identified at the bottom of the S2' pocket that was conveniently filled with either a methyl or a chlorine group on the 5 position of the benzamidine ring. The inhibition constant of the resulting compound (compound IV in the Table 6) was 0.008 μM, which represents approximately a 2500-fold improvement over the first compound from this series. The crystal structure of compound IV or AG1284 complexed with HIV-1 PR was solved, revealing excellent complementarity between the ligand and protein. The ligand forms only 4 hydrogen bonds with either protein functional groups or ordered water molecules, in contrast to the nine hydrogen bonds formed by peptidomimetic LY289612, despite their similar binding affinities. The nonpeptidic character of AG1284 may have contributed to good oral bioavailability and pharmacokinetics in three animal species [43]. Despite very good inhibitory potency on the enzyme level, AG1284 has rather modest antiviral activity in vitro (Table 6). The reason for this discrepancy is unclear but could be related to the low water solubility and higher affinity for membranes, which may effect cell partitioning. A similar lack of correlation between the potency of enzyme inhibition and antiviral activity has been previously observed with other HIV PR inhibitors [11]. Hydroxypyrans and Hydroxycoumarins The lead compounds for the 4-hydroxypyran and 4-hydroxycoumarin series were discovered in biological screens as low potency inhibitors of HIV PR [47–49]. Successful structure solution of both lead compounds with HIV PR enabled rapid optimization of their enzyme inhibitory potencies and anti- HIV activities, and one of these compounds, U96988, has already entered Phase I clinical testing [49,50]. The binding mode of this type of inhibitor differs substantially from the classical peptidomimetic compounds and is somewhat similar to de novo-designed compounds from the cyclic urea series. In the case of 4-hydroxycoumarin, the two oxygen atoms of the lactone functionality are positioned within hydrogen-bonding distance of the two NH amides of Ile50/50' on the flap, replacing the ubiquitous water molecule Wat301. The 4-hydroxyl group (Table 5) is located within hydrogenbonding distance of the two catalytic http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_27.html [4/5/2004 4:46:27 PM]
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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
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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 51 and 52: Document 2 Structural Studies of HI
Page 53 and 54: Document Figure 1 (a) Chemical stru
Page 55 and 56: Document dine (3TC), and 2',3'-dide
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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
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Document Page 67 Biochemical data s
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Document Page 69 determining the me
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Document Chris Tantillo. The work i
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Document Page 72 16. Goldman ME, Nu
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Document 30. Coffin JM. HIV populat
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Document 45. Majumadar C, Abbotts J
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Document reverse transcriptase inhi
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Document 75. Ring CS, Sun E, McKerr
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Document 89. Hughes SH, Arnold E, H
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Document 106. Cirino NM, Cameron CE
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Document 122. Marshall WS, Beaton G
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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 Page 88 transfer (Figure 3
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Document Page 92 The role of the N-
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Document Figure 6 Molscript stereo
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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 Bradykinin Receptor Anta
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Document Page 121 Nearly all cells
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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 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 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 178 studies show that
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Document Figure 5 (a) A cut away vi
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Document Page 182 (SAR) model. The
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Document IX. S2' Interactions Page
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Document Figure 6 (a) The pocket of
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Document Page 189 36. Bode W, Reine
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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 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 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 Page 278 The n=3 chain len
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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 Figure 12 Modeled fit of S
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Document Page 285 number of x-ray s
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Document 36. Leytus SP, Chung DW, K
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Document 54. Broze Jr GJ, Girard TJ
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Document Page 294 70. Seligmann B,
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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 Page 301 domains contribut
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Document Figure 5 Stereo views of 2
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Document A. Chemical Modification P
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Document Page 307 (the exception is
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Document Page 309 site 3 on the sod
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Document Page 314 anemone toxins an
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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 Figure 2 A schematic diagr
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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 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 no known
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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 15. Carter NS, Fairlamb AH
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Document 30. Kim H, Feil I, Verlind
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Document 65. João HC, Williams RJP
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Document 84. Verlinde CLMJ, Hol WGJ
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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 21. Both GW, Sleigh MJ, Co
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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 20 The Integration of Stru
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Document Page 527 function. Iterati
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Document Figure 3 Generation of com
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Document Page 530 screen. For examp
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Document Page 545 protein binding s
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Document Figure 5 Stereo view of th
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Document Lists of Bonding Fragment
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Document Figure 8 Minimized structu
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Document Page 555 N-acylpyrrolidine
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Document 10. Bobbyer DNA, Goodford
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Document 30. O'Shea EK, Rutkowski R
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Document 22 Peptidomimetic and Nonp
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Document Figure 1 Examples of nativ
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Document B. Peptidomimetic Drugs: C
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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 18. Sawyer TK. In: Peptide
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Document MA, Welch KM, Hallak H, Ta
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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 Page 630 177. (a) Bode W,
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Document Page 631 197. Musil D, Zuc
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Document replacements, 563-565 1-am
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Document inhibitor binding, 323, 33
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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 overview, 103-104, 108-109
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Document [Inhibitors] 2-((3,4-dihyd
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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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