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Document Page 3 Based on the avalanche of papers describing the structure-based design of various HIV PR inhibitors, it would be reasonable to assume that, with the exception of saquinavir, all other HIV PR inhibitors that entered the stage of preclinical or clinical development were discovered using the elements of a structurebased approach. From the long list of more than 30 inhibitors considered as clinical candidates [11], currently there are three compounds (saquinavir, ritonavir, and indinavir) already approved by the FDA as anti-HIV drugs. Many factors that are requisite for in vivo activity in AIDS patients can only be predicted a priori in a very general sense. For instance, erratic oral bioavailability in humans, first-pass metabolism, binding to plasma proteins or tissue distribution may disqualify a perfect in vitro inhibitor of HIV replication and such properties can be very poorly predicted by any process of drug design. A potential answer to these problems is the parallel design of several chemically distinct compounds that may have similar in vitro activity but significantly different in vivo properties. The application of protein structure-based design offers such possibilities and in this text the discovery and optimization of different series of potent inhibitors of HIV PR will be discussed. In order to familiarize the reader with the architecture of HIV PR and the properties of its active site, the first paragraphs are devoted to the detailed description of the x-ray structures of the enzyme followed by several examples of inhibitors in a bound conformation. A. Three-Dimensional Structure of HIV PR Retroviral proteases such as HIV PR were tentatively assigned to the aspartic protease family on the basis of putative active-site sequence homology [12]. Mammalian aspartic proteases are bilobal, singlechain enzymes in which each lobe (or domain) contributes an aspartic acid residue to the active site [13]. The active site itself is formed at the interface on the N- and C-terminal domains and exhibits approximate two-fold symmetry. Since the retroviral proteases are only about one-third the size of the two-domain eukaryotic enzymes, they were hypothesized to function as dimers in which each monomer contributes a single aspartic acid to the active site [14]. Obligate homodimeric proteases, in addition to providing a regulatory mechanism to control activation of the enzyme, represent the most efficient use of genetic information which, in retroviruses, is naturally parsimonious. The crystal structures of HIV PR confirmed the predicted dimeric character of the enzyme [15,16] (Figure 1). In all published crystallographic investigations of the unliganded form of the enzyme, the monomers are related to each other by crystallographic two-fold symmetry and are necessarily identical. The general topology of the HIV PR monomer is similar to that of a single-domain http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_3.html [2/29/2004 2:15:00 AM]
Document Figure 1 Stereo view of the α-carbon backbone of HIV PR dimer. (a) The apoenzyme with flaps in the “open” conformation. (b) Inhibited form of HIV PR with flaps in a “closed” conformation. For clarity, the inhibitor is removed from the active site. pepsin-like aspartic protease and consists of antiparallel β-strands and a short, two-turn α-helix connected by loops of varying length. The dimer interface is formed by an antiparallel β-sheet comprising two strands from each monomer. The hydrophobic residues from those β-strands and two symmetry-related α-helices form the core of the dimer. The dimer is further stabilized by a net of hydrogen bonds involving the residues around the catalytic aspartic acids. The active site is formed by the dimer interface and is composed of equivalent contributions of residues from each monomer. The substrate-binding cleft is bound on one side by the active site aspartic acid (Asp25/25') and on the other side by a pair of two-fold related, antiparallel β-hairpin structures, commonly referred to as “flaps.” http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_4.html [2/29/2004 2:15:23 AM] Page 4
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Page 3 and 4: Structure-based Drug Design 14 Stru
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Document Analysis of various HIV-1
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Document Page 54 Table 2) [12,54].
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Document Table 3 HIV-1 RT Amino Aci
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Document Page 67 Biochemical data s
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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 dine) and didanosine (dide
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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 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 65. Gallay P, Swingler S,
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Document 4 Bradykinin Receptor Anta
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Document Page 125 binding site on t
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Document receptor, it has not yet b
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Document Figure 6 Rat and human B2
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Document Figure 9 Composition of te
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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 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 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 protein kinase core is ess
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Document Figure 7 Stereo of zopolre
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Document Cyclotheonamide A (CtA), a
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Document Table 2 Naturally Occurrin
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Document 12 Polypeptide Modulators
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Document A. Chemical Modification P
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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 17. Szelke M. Chemistry of
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Document Table 1 Trypanosomal Targe
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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 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 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 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 462 strains of influe
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Document B. Protein Structure Page
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Document VI. Conclusion Page 480 It
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Document A. The Canyon Page 491 The
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Document Page 495 of the RNA and pr
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Document Figure 5 Some compounds wh
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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 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 Kininogen, 119 high molecu
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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