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Document Figure 5 Comparison of 8-amino and 9-deaza substitutions on guanine. Details are extensively discussed in the text. Cross-hatching schematically indicates the enzyme. Ball and stick diagrams show the inhibitor and key side-chain residues. Nitrogens are dark gray spheres, oxygens are light gray. Arrows indicate hydrogen bonding, with the arrow size showing relative strength. amino group, generating a hydrophobic environment for the group and decreasing binding affinity. Page 162 The carbon-for-nitrogen switch in the 9-deaza variant favors association with PNP by substituting a strong hydrogen bond for the relatively weak one occurring between Asn 243 and guanine. Formation of a simple 8-aminoguanine variant leads to tight binding by giving rise to an extra hydrogen bond between the purine derivative and Thr 242. The combination of the two “improvements”—the carbon-for-nitrogen substitution and the addition of the amino group to position eight—was counterproductive because the carbon in position nine prevented the amino group at http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_162.html (1 of 2) [4/5/2004 5:02:21 PM]
Document position eight from forming the extra bond with Thr 242. In fact, it set up an unfavorable, repulsive clash between the threonine and the added amino group. Page 163 In the absence of detailed structural information, it would have been extremely difficult to explain why affixing the amino group to the carbon in position eight proved unhelpful. But crystallography quickly provided the explanation. 9-Deazaguanine itself would be a better choice for the purine component of an inhibitor. This experience underscores the wonderful economy of the structure-based approach. Without crystallographic data, we might have pursued a logical but unproductive avenue of research much longer than we did. B. Ribose Site The next task was to fill the sugar binding site. The sugar in a nucleoside does not attach to PNP primarily by forming hydrogen bonds, but through hydrophobic attractions. The sugar binding pocket of PNP consists of three hydrophobic amino acids: Phe 200 and Tyr 88 from the same monomer that binds guanine and Phe 159 from the adjacent monomer. Several known inhibitors carried a benzene group attached to position 9 of the purine in place of the sugar in the nucleoside. An initial series of compounds was synthesized to exploit the hydrophobic region in the ribose binding site. A number of 9-substituted 9-deazapurine analogs were prepared with various aromatic, heteroaromatic, and cycloaliphatic substituents. The first 9-deazaguanine derivatives synthesized, such as 9-benzyl-9deazaguanine, were three to six times more potent than the most potent known inhibitor, 8-amino-9-(2thienylmethyl)guanine. The optimum spacer between the purine base and the aromatic substituent proved to be a single methylene group. Crystallographic data showed that generally the planes of the aromatic rings tend to orient in a reproducible conformation. The aromatic groups optimize their interaction with Phe 159 and Phe 200, which results in the classic “herringbone” arrangement reported in a variety of aromatic systems [26]. Inhibitors with cycloaliphatic substituents at N9 of deazaguanine were also as potent as the aromatic analogs. The cycloaliphatic substituents occupied the same general volume as the aromatic groups. As with the aromatic series, the optimum spacer between the 9-deazaguanine and the hydrophobic substituent is one carbon atom. X-ray analysis of the PNP complexes of 9-cyclohexyl-9-deazaguanine, a relatively poor inhibitor, and the complex of 9-cyclohexylmethyl-9-deazaguanine, a potent inhibitor, showed the two cyclohexyl groups occupy approximately the same space in the active site with the purine base pulled out of its optimal position in the former. The chemistry is more straightforward with the aromatic series. From modeling studies, we saw that the sugar binding pocket could be filled more http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_163.html [4/5/2004 5:02:22 PM]
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Document 2 Structural Studies of HI
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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 Page 56 It is also attract
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Document Table 3 HIV-1 RT Amino Aci
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Document ever, once an NNRTI is bou
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Document Chris Tantillo. The work i
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Document reverse transcriptase inhi
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Document dine) and didanosine (dide
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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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Page 149 and 150: Document 4 Bradykinin Receptor Anta
Page 151 and 152: Document Page 121 Nearly all cells
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Page 155 and 156: Document Page 125 binding site on t
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Page 163 and 164: Document Page 133 This initial stag
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Page 169 and 170: Document Figure 6 Rat and human B2
Page 171 and 172: Document Page 141 receptor with int
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Page 175 and 176: Document Figure 9 Composition of te
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Page 185 and 186: Document B. Pharmacology Figure 1 T
Page 187 and 188: Document We determined the structur
Page 189 and 190: Document Figure 3 Previously known
Page 195 and 196: Document large solvent channels and
Page 197: Document IV. Drug Design Progressio
Page 201 and 202: Document Table 1 Inhibition Data fo
Page 203 and 204: Document Page 166 As predicated, th
Page 205 and 206: Document References 1. Parks RE Jr.
Page 207 and 208: Document 17. Ealick SE, Rule SA, Ca
Page 209 and 210: Document 6 Structural Implications
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Page 215 and 216: Document Page 176 0.43 Å) as the c
Page 217 and 218: Document Page 178 studies show that
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Page 221 and 222: Document Page 182 (SAR) model. The
Page 223 and 224: Document IX. S2' Interactions Page
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Page 227 and 228: Document 5. Willenbrock F, Murphy G
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Page 233 and 234: Document 7 Structure—Function Rel
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Document Page 205 enzyme and of phe
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Document protein kinase core is ess
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Document 9 Structural Studies of Al
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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 7 (a) Superposition
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Document Page 412 ture is unlike ot
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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 427 These aromatic di
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Document 39. Saurat JH, Schfferli J
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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 33. Szente BE, Johnson HM.
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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 Page 555 N-acylpyrrolidine
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Document 30. O'Shea EK, Rutkowski R
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Document Acknowledgments Page 620 I
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Document Med Biol 1991; 306:9-21; (
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Document Page 629 ML, Clare M, Decr
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Document son AH, Drummond AH, Huxle
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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 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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