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Document Page 22 water mimic was used and in subsequent synthetic targets the cyclohexanone ring was enlarged to a 7membered ring to incorporate a diol functionality. This target was further modified to a cyclic urea, which can be symmetrically substituted from both nitrogens without creating unnecessary stereocenters. The crystal structures of about 10 cyclic-urea-based inhibitors with HIV PR were solved [42]. In all cases, the C2 symmetric inhibitors bind to the HIV PR active site with the diad symmetry axes of the protease and the compounds being nearly coincident. The 7-membered ring of the inhibitors is roughly perpendicular to the plane of the catalytic aspartates 25/25' and both hydroxyl groups of the diol are positioned to interact with their carboxylates. The carbonyl oxygen of the inhibitors accepts hydrogen bonds from backbone amides of symmetrically distributed residues Ile50/50' of the flap. In the structure of DMP323, symmetrically substituted moieties of hydroxymethylbenzyls and phenylalanines extend towards the S2/S2' and S1/S1' subsites respectively and are involved in van der Waals interactions with the hydrophobic residues of these pockets [42]. The interaction of DMP323 with the residues of HIV PR are restricted to the central four specificity subsites of the active site. Despite this limited area of hydrophobic interaction and hydrogen bonding restricted to the central cyclic urea functionality, DMP323 is a very potent inhibitor of HIV PR with good antiviral activity in vitro (Table 5). The limited solubility of this compound was perhaps responsible for erratic oral availability in humans, and after short trials, DMP323 was withdrawn from the clinical investigation. Nevertheless, the discovery of this class of compounds represents a very interesting and, by now, classical example of de novo structure-based drug design. Design and Structure of AG1284 Another compound discovered by the application of de novo structure-based design is AG1284 [43]. In the initial design of a lead compound, the nonpeptidic hydroxyethyl-t-butylbenzylamide portion of LY289612 occupying the S1' and S2' subsites was retained as a “starting module.” In attempting to fill the pockets related by the dimer two-fold symmetry it was discovered that, by extending a two-carbon fragment from the central hydroxyl carbon, the S1 subsite could be accessed by an aromatic ring. The ring was oriented orthogonal to the observed P1 phenyl group of the classical inhibitors and this allowed further extension off the ortho position towards the S2 subsite. In order to maintain the critical hydrogen bond to the flap water Wat301, in the initial compounds an acylated amino group was used, replaced in subsequent designs by a benzamide functionality. In this model, the geometry of the hydrogen bonds to the flap water was somewhat perturbed, and the nitrogens of the t-butyl amides on both sides of the compound were in a position to interact favorably with solvent, http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_22.html [4/5/2004 4:45:29 PM]
Document Page 23 potentially lowering the desolvation penalty. The absence of hydrogen-bonding interactions with the carbonyl oxygens of Gly27/27' was viewed as a positive factor, since the accumulated structural and mechanistic information suggested that formation of these hydrogen bonds may not be energetically favorable [23]. The compound was synthesized as a racemic mixture of two enantiomers of the central hydroxymethyl group and had the inhibition constant of 24 μM. Despite the modest binding constant of compound II (Table 6) and very low water solubility, the co-crystal structure with HIV PR was solved at 2.3 Å resolution, providing a critical starting point for further design. The inhibitor was found to bind largely as anticipated with the two aromatic rings occupying the S1 and S1' subsites and the two benzamide carbonyls forming hydrogen bonds to the flap water Wat301. Both benzamide nitrogens interact via a string of highly ordered water molecules with the amide nitrogens of Asp29/29'. The crystal structure of the complex indicated that the S enantiomer was the more active component of the racemic mixture and this was confirmed by stereoselective synthesis of subsequent compounds [44]. In the subsequent designs, the ortho-substituted benzyl rings were consecutively replaced by larger naphthyl groups that occupied more of the S1–S3 and S1'–S3' subsites. The increased area of hydrophobic interactions with the residues in these subsites was reflected in a substantial improvement in the http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_23.html [4/5/2004 4:45:41 PM]
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Page 11 and 12: Document TF—transframe, PR—prot
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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 67 and 68: Document Page 54 Table 2) [12,54].
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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 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 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 receptor, it has not yet b
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Document Page 135 might be jointly
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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 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 20. Murphy G, Docherty AJP
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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 Figure 3 (a) Ternary compl
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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 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 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 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 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 Figure 8 The catalytic mac
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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 5-Methoxytryptamine 19.0 9
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Document Figure 12 Predicted bindin
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Document Page 388 nosine proved to
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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 39. Saurat JH, Schfferli J
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Document 74. Bender PE, Lee JC., ed
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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 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 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 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 Figure 3 Generation of com
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Document Page 545 protein binding s
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Document 10. Bobbyer DNA, Goodford
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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 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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