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Document Page 34 complexed with various inhibitors offers a unique opportunity for the development of such computational methods if the structural data can be coupled with thermodynamic measurements of inhibitor-protein binding. These include direct measurements by microcalorimetry of the association constant, K, and in addition the enthalpy, entropy, heat capacity, and stoichiometry of binding. The combination of such thermodynamic and structural data will lead to a more precise understanding of the factors that influence binding and, ultimately, will lead to new general design principles that can be applied to drug discovery in the area of AIDS as well as other challenging diseases. Acknowledgments I wish to thank all my co-workers from Agouron who contributed to these studies, in particular J. Davies, S. Reich, M. Melnick, V. Kalish, A. Patick, L. Musick, and B-W. Wu. Steven Kaldor from Ely Lilly is acknowledged for his contribution in designing AG1343 (nelfinavir). I would like to thank Richard Ogden for critical reading of the manuscript and D. Olson for expert assistance in preparing the manuscript. References 1. Mitsuya H, Yarchoan R Broder S. Molecular Targets for AIDS therapy. Science 1990; 249:1533–1543. 2. DeClerq E. Toward improved anti-HIV chemotherapy: Therapeutic intervention with HIV infections. J. Med. Chem. 1995; 38:2491–2517. 3. Tomaselli AG, Howe JW, Sawyer TK, Wlodawer A, Henrikson RL. HIV-1 protease as a target for drug design. Chimica Oggi 1991; 9:6–14. 4. Ding J, Das K, Yadav PNS, Hsiou Y, Zhang W, Hughes SH, Arnold E. Structural studies of HIV-1 reverse transcriptase and implications for drug design. In: Structure-Based Drug Design. New York: Marcel Dekker 1996, in press. 5. Perno CF, Bergamini A, Pesce CD. Inhibition of the protease of human immunodeficiency virus blocks replication and infectivity of the virus in chronically infected macrophages. J. Infect. Dis. 1993; 168:1148–1156. 6. Kohl NE, Emini EA, Schleif WA, Davis LJ, Heimbach JC, Dixon RAF, Scolnick EM, Sigal, IS. Active human immunodeficiency virus protease is required forviral infectivity. Proc. Natl. Acad. Sci. USA, 1988; 85:4186–4690. 7. McQuade TK, Tomasselli AG, Liu L, Karacostas V, Moss B, Sawyer TK, Heinrikson RL, Tarpley WG. A synthetic HIV-1 protease inhibitor with antiviral activity arrests HIV-like particle maturation. Science 1990; 247:454–456. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_34.html (1 of 2) [4/5/2004 4:46:59 PM]
Document 8. Kaplan AH, Zack JA, Knigge M, Paul DA, Kempf DJ, Norbeck DW, Swanstrom R. Partial inhibition of the human immunodeficiency virus type 1 protease results in aberrant virus assembly and the formation of noninfectious particles. J. Virol. 1993; 67:4050–4055. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_34.html (2 of 2) [4/5/2004 4:46:59 PM]
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Page 81 and 82: Document Page 67 Biochemical data s
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Document 45. Majumadar C, Abbotts J
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Document dine) and didanosine (dide
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Document 163. Lacey SF, Larder BA.
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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 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 We determined the structur
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Document large solvent channels and
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Document 6 Structural Implications
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Document 7 Structure—Function Rel
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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 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 29. Baker ME. Genealogy of
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Document protein kinase core is ess
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Document 12 Polypeptide Modulators
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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 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 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 Table 1 Trypanosomal Targe
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Document Table 2 Three-Dimensional
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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 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 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 Figure 1 A schematic diagr
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Document Page 462 strains of influe
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Document Figure 5 Some compounds wh
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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 Page 629 ML, Clare M, Decr
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Document Page 631 197. Musil D, Zuc
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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 [Interleukin-1] homology w
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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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