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Document Page 20 S-naphthylcysteine derived side chains in P1 resulted in a substantial increase in the inhibition constants [37]. The increase in the binding affinity to the low picomolar range in enzyme inhibition assay, allowed for subsequent truncation of the P3 quinoline moiety. The final compound from this miniseries (compound III in Table 4) consisted of the ortho-substituted benzamide in the P1' and P2', Snaphthylcysteine in P1 and asparagine in P2. Despite reduced molecular weight, the inhibition constant of this compound for HIV PR was comparable to LY289612. The observation that a larger, nonpeptidic moiety in the P1 could eliminate the need for the P3 side chain led to hybrid molecules that incorporated ring structures as the P2 component and maintained the P1 S-naphthylcysteine side chain of compound III. In this miniseries several bicyclic functionalities were modeled as the P2 substituents and one example, compound IV utilizing a tetrahydroquinoline group, is shown in Table 4 [38]. In subsequent modeling, it was noticed that the P2 bicyclic functionality might be replaced by 2,3-disubstituted phenyl rings. In particular, a methyl substitution in position 2 would increase the area of hydrophobic interaction in a manner previously observed in the isophthal series. Addition of a hydrophilic functionality attached at position 3 could increase the solubility of the compound and contribute to the binding constant by forming a hydrogen bond with the carboxylate oxygen of Asp30. A compound with a 2-methyl-3-hydroxy substitution pattern was synthesized and showed an improved inhibition constant of 3 nM in the HIV PR enzyme assay (Table 4). The crystal structure of compound V with HIV PR was solved and indicated the predicted binding mode with the possibility of a stacking interaction between the P2 phenyl and the P1 thio-naphthyl groups and the expected hydrophobic and hydrogen-bonding interactions of the P2 moiety with the protein side chains in the corresponding specificity pocket [38]. As with the optimized compounds from other series, compound V suffered from low aqueous solubility. The replacement of the P1' aryl group by the basic amine-containing decahydroisoquinoline dramatically increased the solubility and allowed for truncation of the P1 S-naphthylcysteine side chain to S-phenylcysteine without any loss of inhibitory activity. The resulting compound VI, AG1343 or nelfinavir, has an inhibition constant of 1.9 nM in the HIV PR enzyme assay and respectable antiviral activity with an IC 90 of 60 nM [39]. The nonpeptidic character, pH-dependent solubility profile, and the small molecular weight of nelfinavir may contribute to its good pharmacokinetic profile in humans [40,41]. Currently, this compound is being tested and is in the advanced phase of clinical trials. The crystal structure of nelfinavir bound to the active site of HIV PR is shown in Figure 5. The general binding mode of this compound, in particular the path of the backbone, is similar to the binding mode of peptidyl inhibitors. Nevertheless, the lack of any peptide bonds utilizing naturally occurring amino http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_20.html [4/5/2004 4:44:58 PM]
Document Figure 5 Stereo view AG1343 (nelfinavir) bound to the active site of HIV PR. Page 21 acids qualifies nelfinavir to be a member of the group of nonpeptidic inhibitors of HIV PR. The unique, and perhaps crucial hydrogen-bonding interaction of the P2 hydroxyl group with the carboxylate oxygen of Asp30, combined with the smaller area of hydrophobic contacts in the S1 and S3 specificity subsites are the principal differences from other clinically active HIV PR inhibitors and may contribute to a distinct resistance pattern and point to additional utility of nelfinavir in the treatment of AIDS. Design and Structure of DMP323 A cyclic urea-containing HIV PR inhibitor, DMP323, was discovered using de novo structure-based design principles. Similar to the concept of Erickson and his co-workers from Abbott Laboratories, the group from DuPont-Merck attempted to take advantage of the two-fold symmetry of HIV PR in designing compounds that maintained the interaction of the diol with the catalytic aspartic acids 25/25' and at the same time were able to functionally displace the ubiquitous flap water molecule Wat301. They hypothesized that incorporation of the binding features of this structural water molecule into an inhibitor would be beneficial because of the entropic gain due to its displacement and because the conversion of a flexible linear inhibitor into a rigid, cyclic structure with restricted conformation should provide an additional, positive entropic effect. In the initial design, a cyclohexanone with the ketone oxygen as the structural http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_21.html [4/5/2004 4:45:10 PM]
Page 1 and 2: netLibrary - eBook Summary Universi
Page 3 and 4: Structure-based Drug Design 14 Stru
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Page 11 and 12: Document TF—transframe, PR—prot
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Page 17 and 18: Document Page 13 of the active-site
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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 and 54: Document Figure 1 (a) Chemical stru
Page 55 and 56: Document dine (3TC), and 2',3'-dide
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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
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Document Page 61 now clear that the
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Document Page 63 most of the amino
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Document Page 65 cal properties of
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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 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 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 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. Vink C, Plasterk RHA. T
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Document Page 115 21. Kulkosky J, J
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Document 44. Cushman M, Sherman P.
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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 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 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 5. Willenbrock F, Murphy G
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Document 20. Murphy G, Docherty AJP
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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 46. Ribas dePoplana L, Fot
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Document Figure 1 (Continued) this
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Document Page 218 The catalytic loo
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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 2. Lee AYW, Chung SK, Chun
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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 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 Page 288 Additionally, the
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Document Page 290 5. Kaiser B, Haup
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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 Page 329 binding involves
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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 48. Powers JC, Harley AD,
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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 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 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 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 Figure 9 A solvent-accessi
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Document accommodate a variety of d
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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 Figure 3 Generation of com
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Document Page 530 screen. For examp
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Document Page 537 ries, holds the p
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Document 21 Structure-Based Combina
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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 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 97; (e) Fujii I, Nakamura
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Document Med Biol 1991; 306:9-21; (
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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 Kininogen, 119 high molecu
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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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