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Document Page 30 mutation of Asp30/30' to asparagine seems to be specific for nelfinavir and was initially observed in cellculture sequential passage experiments [62]. Recently, the same phenotypic change was confirmed as the predominant mutation in the resistant variants appearing in AIDS patients exposed to low doses of this HIV PR inhibitor [64]. The molecular basis of resistance involving this mutation can be rationalized as follows: in the crystal structure of nelfinavir with the wild type HIV PR, the 3-hydroxyl group of the 2,3-substituted phenyl group is within hydrogen-bonding distance of the carboxylate oxygen of Asp30 in the S2 subsite. Due to the expected coulombic character of this interaction, the hydrogen bond formed with the negatively charged carboxylate of Asp30 would be expected to be a relatively strong one. The change of the negatively charged carboxylate of Asp30/30' to the amide oxygen of the asparagine side chain should reduced the strength of this interaction. Apparently the loss in the enthalpic contribution to the free energy of binding is only partially balanced by the entropic gain caused by the difference in desolvation of a charged vs. neutral side chain of the receptor, leading to decreased binding affinity of nelfinavir and eventually to viral resistance. An additional resistance-causing mutation that qualifies as a primary mutation involves the change of Gly48/48' to valine. This particular mutation seems to be specific for saquinavir and was observed both in cell-culture sequential passage experiments and in AIDS patients exposed to this inhibitor [61,65]. Located on the lower strands of the active-site forming flaps, Gly48/48' can be considered a part of the S4/S4' subsites. The replacement of the glycine hydrogen by the rigid side chain of valine has most likely a dual effect: first it has a direct impact on the interaction of the quinoline moiety of saquinavir with the active site of HIV PR, and second it may change the mobility of the flaps, which in turn will effect the binding kinetics of the natural substrates or inhibitors. Although none of the other clinically tested inhibitors form any interaction with this part of the flap, the HIV variants with mutation of Gly48/48' seem to be cross-resistant to all compounds, which is reflected by a 3–5-fold reduction of their antiviral activity [55,62]. While the effect of primary mutations on reduced binding affinities of inhibitors can be at least partially explained in view of the accumulated structural data, the function of secondary, or compensatory mutations in the resistant HIV PR is difficult to rationalize as yet. The predominant compensatory mutations observed in the resistant variants involve residues Leu63/63', Ala71/71', Met46/46', Asn88/88', Leu10/10', and Leu90/90' (Figure 8) [60,63]. Changes of these residues alone do not confer viral resistance, but their appearance increases the viability of the virus carrying the primary mutations in the active site of protease. All these residues are located far away from the active site of HIV PR do not participate in any apparent way in the inhibitor binding and it seems unlikely that they form a longrange interaction with the natural http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_30.html [4/5/2004 4:46:41 PM]
Document Figure 8 Cartoon representation of the HIV PR dimer. The sites of compensatory mutations are indicated. substrate. Also, the reported compensatory mutations are conservative in nature and have no effect on the overall distribution of atomic charges on the surface of HIV PR. Page 31 Sequence polymorphism at the Leu63/63' position, located on the surface at the base of HIV PR, has been observed in clinical isolates of the virus not exposed to any HIV PR inhibitors. Variations of Ala71/71', where the side chains are buried very close to Leu63/63', are less commonly found in clinical isolates. After a prolonged challenge by HIV PR inhibitors, Leu63/63' changes to proline and Ala71/71' to valine. The side chains of Met46/46' are fully exposed to solvent and these residues are located on the βhairpins that form the active side flaps. It has been speculated that the compensatory change of Met46/46' to isoleucine or phenylalanine may affect the dynamics of the flap movement, which in turn could influence the rates of catalytic activity of HIV PR impeded by the primary mutations in the active site [58]. Any changes to Asn88/88' and Leu90/90', buried in the body of HIV PR, most likely affect the structural stability of the enzyme. The side chains of Asn88/88' form buried hydrogen bonds and replacement of this residue by aspartic acid or serine not only eliminates some of these bonds but also introduces unfavorable interactions in the core of HIV PR. Similarly, Leu90/90' is buried in a tight hydrophobic space close to the “fireman's grip” motif, which http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_31.html (1 of 2) [4/5/2004 4:46:51 PM]
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Page 3 and 4: Structure-based Drug Design 14 Stru
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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 39 and 40: Document 8. Kaplan AH, Zack JA, Kni
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Page 45 and 46: Document 47. Tummino PJ, Ferguson D
Page 47 and 48: Document 60. Condra JH, Schleif WA,
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
Page 57 and 58: Document Figure Continued Page 45 r
Page 59 and 60: Document Figure 2 Ribbon diagrams o
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
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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Page 81 and 82: 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 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 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 Page 129 tolerated by the
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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 Page 214 viruses. Specific
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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 18. Wilson DK, Tarle I, Pe
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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 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 312 In peptide—prot
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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 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 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 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 B. Protein Structure Page
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Document Figure 5 (a) Stereo image
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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 VI. Conclusion Page 480 It
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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 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 3 Generation of com
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Document Acknowledgments Page 620 I
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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 Phosphoglycerate kinase (P
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