The Future

4.04.4.1 High-Throughput Crystallography

Crystallography continues to undergo dramatic changes.168 New and improved methodologies are continually evolving in robotics, x-ray sources, computational power, crystal-growing screens, molecular genetics, and preparation of adequate sources of desired targets. More importantly, these improved technologies are integrated in both industrial and academic laboratories. The advent of companies specifically organized and funded to perform high-throughput crystallography has been expanding. Structural genomic programs abound and readily feed into SBDD applications.168 Will the future for structure-based drug discovery live up to its elegance and early successful efforts in discovering new therapeutic agents? The answer will be 'yes,' and even better than that!

4.04.4.2 Combinatorial Chemistry, High-Throughput Screening (HTS), and Structure-Based Drug Design

The norm, especially in the largest pharmaceutical companies, has been to make sure any new technologies (fads?) for discovering lead molecules found in a competitor's company must be had by all, just in case. Looking back at the mania that arose from the birth of combinatorial chemical libraries coupled with HTS, one must ask, as I have heard said a number of times from colleagues, ''Was all the excitement and efforts directed toward combinatorial chemistry/high-throughput screening really worth it?'' The answer at this time is no. As of 2002 only a few have entered preclinical and clinical trials.170 There have been a number of road blocks with screening of combinatorial libraries. The first is that HTS usually employs a single purified target protein or receptor isolated from cellular contents. When only a single target is assayed, the results are devoid of the robust milieu pharmacologists used with whole-cell or quick looks in vivo in rats. The second is that current HTS methodologies identify large numbers of leads. However, most leads are too insoluble to become drugs. This problem multiplies when chemists are brought in to make analogs with suitable ADME properties. It is now in vogue to use the Lapinski rule of five and SBDD findings for a given system to design the next round of libraries.

Some thought at the beginning - a one-million combinatorial library would contain every known drug. It was a surprise that such a library actually had no known drugs. Campbell has noted a logical reason for the failure of large libraries. ''One factor in this perceived lack of success may be that combinatorial chemistry has been widely used to generate thousands of similar compounds, but limited synthetic options have not allowed access to the rich molecular architectures often required for interaction with biological targets. In response, emphasis has now shifted to building compound files with maximum structural richness and diversity, since designed libraries should have higher hit rates.''171

A recent review by Kubinyi summarizes the problems with combinatorial chemistry with suggestions for success in the future. ''Lack of success with early combinatorial chemistry and HTS approaches resulted from inappropriate compound selection. We are now aware that screening compounds should be either 'lead-like' or 'drug-like' and have the potential to be orally available. However, there is a growing tendency to misuse such terms and to overestimate their importance, and to overemphasize ADME problems in clinical failure. Sometimes, this goes hand-in-hand with an uncritical application of high-throughput in silico methods. Structure-based and computer-aided approaches can only be as good as the medicinal chemistry they are based on. The search for new drugs, especially in lead optimization, is an evolutionary process that is only likely to be successful if new methods merge with classical medicinal chemistry knowledge.''172 SBDD and combinatorial chemistry integration are at hand but it is too early to predict the success of this marriage.

4.04.4.3 The National Institutes of Health Structural Biology Road Map, Canonical Structures for Protein Folding, and Structure-Based Drug Design

The NIH Road Map for Structural Biology as provided in the NIH website states it ''is a strategic effort to create a 'picture' gallery of the molecular shapes of proteins in the body. This research investment will involve the development of rapid, efficient, and dependable methods to produce protein samples that scientists can use to determine the 3D structure, or shape, of a protein. The new effort will catalyze what is currently a hit-or-miss process into a streamlined routine, helping researchers clarify the role of protein shape in health and disease.'' Clearly an effort to sample the whole human genome is in progress. It is hoped that there will be a definitive number of folds that proteins form (canonical structures). One will then be able to acquire a desired protein target in three dimensions directly from the human genome. This knowledge of the active site for any protein in the genome has been acknowledged as the primary future economic engine for the future of biotechnology.173-176 SBDD will therefore have the key focus for the future of drug discovery.

4.04.4.4 Real-Time Crystallography

Protein crystallography is normally a static tool that visualizes end-state structures at stable free energies and cannot be used to follow biological reactions in real time. However, in the 1980s Ringe and Petsko177 studied protein dynamics by x-ray crystallography and Hajdu and colleagues used Laue diffraction that is capable of recording entire protein crystal data sets in a millisecond.178 Recently, picosecond time-resolved x-ray crystallography has been able to probe protein function in real time.179 When combined with low-temperature techniques, such methods could be used to determine the structures of catalytic intermediates. With this development it will be possible for medicinal chemists to use SBDD to discover transition-stated analogs with a probable higher rate of success than with the static receptor design methods. This technique might also be valuable in assaying flexible binding sites during the initial binding of inhibitors or substrates.

4.04.4.5 Single-Molecule Imaging: Determining the Three-Dimensional Structure of Receptors without the Need to Crystallize Them

Electron microscopy is another principal method of macromolecular structure determination that uses scattering techniques, as discussed in Section 4.04.1.2.6. The most important difference between electron microscopy and x-ray crystallography is that electron microscopy specimens are 1-10 nm thick, whereas scattering or absorption of a similar fraction of an illuminating x-ray beam requires crystals that are 100-500 mm thick. The second advantage is that electrons are readily focused while x-rays cannot be directly imaged. As a result, Henderson and Baker61 point out: ''electron lenses are greatly superior to x-ray lenses and can be used to produce a magnified image of an object as easily as a diffraction pattern. This then allows the electron to be switched back and forth instantly between imaging and diffraction modes so the image of a single molecule at any magnification can be obtained as conveniently as the electron diffraction pattern of a thin crystal.'' The number of inelastic events for electrons scattered by biological structures at all electron energies of interest exceeds the number of elastic events by a factor of 3-4, so each elastically scattered electron deposits 60-80 eV of energy. The amount of information in a single biological image of a macromolecule is therefore limited. Unfortunately, at this time, the 3D atomic structure cannot be determined from a single molecule but theoretically requires the averaging of the information from at least 10 000 molecules: this has not yet been achieved in practice.180 Obviously, crystals used for x-ray or neutron diffraction contain many magnitudes of diffracting molecules.

Henderson and Baker comment on the current trends in the field61: ''(1) increased automation, including the recording of micrographs, the use of spotscan procedures in remote microscope operation,181,182 and in every aspect of image processing; (2) production of better electronic cameras (e.g., CCD or pixel detectors); and (3) increased use of dose-fractionated, tomographic tilt series, to extend EM studies to the domain of larger supramolecular and cellular structures.''183,184 The increased capabilities in the future of electron microscopy may well enable a large number of interesting biological targets to be imaged where crystallography cannot be employed. If these advances are successful we may one day see imaging of a single macromolecule of biological interest for SBDD. This would be the holy grail for structural biology.

References

1. Ehrlich, P. Int. Arch. Allergy Appl. Immunol. 1954, 5, 67-86.

2. Cushman, D. W; Cheung, H. S.; Sabo, E. F; Rubin, B.; Ondetti, M. A. Fed. Proc. 1979, 38, 2778-2782.

3. Cushman, D. W; Cheung, H. S.; Sabo, E. F; Ondetti, M. A. Prog. Cardiovasc. Dis. 1978, 21, 176-182.

4. Cushman, D. W; Cheung, H. S.; Sabo, E. F; Ondetti, M. A. Biochemistry 1977, 16, 5484-5491.

5. Patchett, A. A.; Harris, E.; Tristram, E. W; Wyvratt, M. J.; Wu, M. T; Taub, D.; Peterson, E. R.; Ikeler, T. J.; Ten, B. J.; Payne, L. G. et al. Nature 1980, 288, 280-283.

7. Arndt, U. W; Leigh, J. B.; Mallett, J. F; Twinn, K. E. J. Sci. Instrum. 1969, 2, 385-387.

8. Arndt, U. W; Crowther, R. A.; Mallett, J. F J. Sci. Instrum. 1968, 1, 510-516.

10. Levinthal, C. Ann. NY Acad. Sci. 1984, 426, 171-180.

11. Abraham, D. J. X-Ray Crystallography and Drug Design. In Computer-Aided Drug Design; Perun, T J., Propst, C. L., Eds.; Marcel Dekker: New York, 1989, pp 93-132.

12. Kendrew, J. C.; Bodo, G.; Dintzis, H.; Parrish, R.; Wyckoff, H.; Phillips, D. Nature 1958, 181, 662-666.

13. Richards, F M. Methods Enzymol. 1985, 115, 145-154.

14. Wyckoff, H. W; Hardman, K. D.; Allewell, N. M.; Inagami, T; Tsernoglou, D.; Johnson, L. N.; Richards, F M. J. Biol. Chem. 1967, 242, 3749-3753.

15. Wyckoff, H. W; Hardman, K. D.; Allewell, N. M.; Inagami, T; Johnson, L. N.; Richards, F M. J. Biol. Chem. 1967, 242, 3984-3988.

16. Rubin, B.; Richardson, J. S. Biopolymers 1972, 11, 2381-2385.

17. Martz, E.; Francoeur, E. History of Visualization of Biological Macromolecules 21, 2004. http://www.umass.edu/microbio/rasmol/history.htm (accessed Aug 2006).

18. Richardson, J. S.; Richardson, D. C.; Thomas, K. A.; Silverton, E. W; Davies, D. R. J. Mol. Biol. 1976, 102, 221-235.

19. Connolly, M. L. Molecular Surfaces: A Review - Part 4. Molecular Graphics 22, 1996. http://www.netsci.org/ (accessed Aug 2006).

21. Barry, C. D.; North, A. C. Biochem. J. 1971, 121, 3P.

22. Katz, L.; Levinthal, C. Annu. Rev. Biophys. Bioeng. 1972, 1, 465-504.

23. Levinthal, C.; Wodak, S. J.; Kahn, P.; Dadivanian, A. K. Proc. Natl. Acad. Sci. USA 1975, 72, 1330-1334.

25. Collins, D. M.; Cotton, E A.; Hazen, E. E., Jr.; Meyer, E. E, Jr.; Morimoto, C. N. Science 1975, 190, 1047-1053.

26. Porter, T K. Comput. Graphics 1978, 12, 282-285.

27. Eeldmann, R. J.; Bing, D. H.; Eurie, B. C.; Eurie, B. Proc. Natl. Acad. Sci. USA 1978, 75, 5409-5412.

29. Palmer, T. C.; Hausheer, E H.; Saxe, J. D. J. Mol. Graph. 1989, 7, 160-168.

31. Johnson, C. K. ORTEP-U, a Fortran Thermal-Ellipsoid Plot Program for Crystal Structure Illustrations; Technical Report ORNL-5138; Oak Ridge National Laboratory: Tennessee, 1976.

32. Diamond, R. Acta Crystallogr. 1971, A27, 436-452.

33. Diamond, R. Biomol. Struct. Conform. Funct. Evol. 1981, 1, 567-588.

34. Diamond, R. Bilder: An Interactive Graphics Program for Biopolymers. In Computational Crystallography; Sayre, D., Ed.; Clarendon Press: Oxford, 1981, pp 318-325.

35. Lesk, A. M.; Hardman, K. D. Science 1982, 216, 539-540.

36. Lesk, A. M.; Hardman, K. D. Methods Enzymol. 1985, 115, 381-390.

37. Lesk, A. M. Protein Architecture: A Practical Approach; IRL Press: Oxford, 1991.

38. Jones, T. A. ERODO: A Graphics Eitting Program for Macromolecules. In Computational Crystallography; Sayre, D., Ed.; Clarendon Press: Oxford, 1981, pp 303-317.

39. Jones, T A. J. Appl. Crystallogr. 1978, 11, 268-272.

40. Jones, T A. Methods Enzymol. 1985, 115, 157-171.

41. Roussel, A.; Eontecilla-Camps, J. C.; Cambillau, C. J. Mol. Graph. 1990, 8, 86-88, 91.

42. Goodford, P. J. J. Med. Chem. 1985, 28, 849-857.

43. Langridge, R.; Eerrin, T E.; Kuntz, I. D.; Connolly, M. L. Science 1981, 211, 661-666.

44. Shoichet, B. K.; Kuntz, I. D. Protein Eng. 1993, 6, 723-732.

45. Shoichet, B. K.; Stroud, R. M.; Santi, D. V; Kuntz, I. D.; Perry, K. M. Science 1993, 259, 1445-1450.

47. Marshall, G. Professor of Biochemistry and Molecular Biophysics at Washington University's School of Medicine, 2005. http://bp.wustl.edu/ #program-faculty (accessed Aug 2006).

48. Cramer, R. D., III.; Patterson, D. E.; Bunce, J. D. Prog. Clin. Biol. Res. 1989, 291, 161-165.

49. Williamson, M. P; Havel, T E; Wuthrich, K. J. Mol. Biol. 1985, 182, 295-315.

50. Pervushin, K.; Riek, R.; Wider, G.; Wuthrich, K. Proc. Natl. Acad. Sci. USA 1997, 94, 12366-12371.

51. Craik, D. J.; Clark, R. J. NMR and Drug Discovery. In Burger's Medicinal Chemistry and Drug Discovery; 6 th ed.; Abraham, D. J., Ed.; John Wiley: Hoboken, NJ, 2003; Vol. 1, pp 507-582.

52. Coluquhoun, D.; Shelley, C.; Hatton, C.; Unwin, N.; Sivilotti, L. Nicotenic Acetyl Choline Receptors. In Burger's Medicinal Chemistry and Drug Discovery; 6th ed.; Abraham, D. J., Ed.; John Wiley: Hoboken, NJ, 2003; Vol. 1, pp 357-406.

53. Henderson, R.; Baldwin, J. M.; Ceska, T A.; Zemlin, E; Beckmann, E.; Downing, K. H. J. Mol. Biol. 1990, 213, 899-929.

54. Henderson, R.; Schertler, G. E Philos. Trans. R. Soc. Lond. B Biol. Sci. 1990, 326, 379-389.

55. Westkaemper, R. B.; Glennon, R. A. Pharmacool. Biochem. Behav. 1991, 40, 1019-1031.

56. Dubochet, J.; Adrian, M.; Chang, J. J.; Homo, J. C.; Lepault, J.; McDowall, A. W; Schultz, P Q. Rev. Biophys. 1988, 21, 129-228.

57. Amos, L. A.; Henderson, R.; Unwin, P N. Prog. Biophys. Mol. Biol. 1982, 39, 183-231.

58. Walz, T; Grigorieff, N. J. Struct. Biol. 1998, 121, 142-161.

59. Baker, T. S.; Olson, N. H.; Euller, S. D. Microbiol. Mol. Biol. Rev. 1999, 63, 862-922.

60. Erank, J. Three-Dimensional Electron Microscopy of MacromolecularAssemblies; Academic Press: San Diego, CA, 1996.

61. Henderson, R.; Baker, T S. Electron Cryomicroscopy of Biological Macromolecules. In Burger's Medicinal Chemistry and Drug Discovery; 6 th ed.; Abraham, D. J., Ed.; John Wiley: Hoboken, NJ, 2003; Vol. 1, pp 611-632.

62. Muegge, I.; Martin, Y C.; Hajduk, P. J.; Eesik, S.W.J. Med. Chem. 1999, 42, 2498-2503.

63. Rotstein, S. H.; Murcko, M. A. J. Med. Chem. 1993, 36, 1700-1710.

64. Wlodawer, A.; Vondrasek, J. Annu. Rev. Biophys. Biomol. Struct. 1998, 27, 249-284.

65. Lipscomb, W N.; Reeke, G. N., Jr.; Hartsuck, J. A.; Quiocho, E A.; Bethge, P. H. Philos. Trans. R. Soc. LondB Biol. Sci. 1970, 257, 177-214.

66. Quiocho, E A.; Bethge, P H.; Lipscomb, W N.; Studebaker, J. E; Brown, R. D.; Koenig, S. H. Cold Spring Harb. Symp. Quant. Biol. 1972, 36, 561-567.

67. Abraham, D. J. Intra Sci. Chem. Rep. 1974, 8, 1-9.

68. Sobell, H. M.; Jain, S. C.; Sakore, T D.; Ponticello, G. Cold Spring Harb. Symp. Quant. Biol. 1972, 36, 263-270.

69. Matthews, D. A.; Alden, R. A.; Bolin, J. T; Ereer, S. T; Hamlin, R.; Xuong, N.; Kraut, J.; Poe, M.; Williams, M.; Hoogsteen, K. Science 1977, 197, 452-455.

70. Bolton, W; Perutz, M. E Nature 1970, 228, 551-552.

71. Eermi, G.; Perutz, M. E; Shaanan, B.; Eourme, R. J. Mol. Biol. 1984, 175, 159-174.

72. Perutz, M. E; Muirhead, H.; Cox, J. M.; Goaman, L. C. Nature 1968, 219, 131-139.

74. Huang, Y; Pagnier, J.; Magne, P; Baklouti, E; Kister, J.; Delaunay, J.; Poyart, C.; Eermi, G.; Perutz, M. E Biochemistry 1990, 29, 7020-7023.

75. Nagai, K.; Perutz, M. E; Poyart, C. Proc. Natl. Acad. Sci. USA 1985, 82, 7252-7255.

76. Perutz, M. E; Pulsinelli, P. D.; Ranney, H. M. Adv. Exp. Med. Biol. 1972, 28, 3-18.

77. Pulsinelli, P. D.; Perutz, M. E; Nagel, R. L. Proc. Natl. Acad. Sci. USA 1973, 70, 3870-3874.

78. Perutz, M. E; Pulsinelli, P.; Eyck, L. T; Kilmartin, J. V; Shibata, S.; Iuchi, I.; Miyaji, T; Hamilton, H. B. Nat. New Biol. 1971, 232, 147-149.

79. Weatherall, D. J.; Clegg, J. B.; Callender, S. T.; Wells, R. M.; Gale, R. E.; Huehns, E. R.; Perutz, M. E.; Viggiano, G.; Ho, C. Br. J. Haematol. 1977, 35, 177-191.

80. Honig, G. R.; Vida, L. N.; Rosenblum, B. B.; Perutz, M. E; Eermi, G. J. Biol. Chem. 1990, 265, 126-132.

81. Perutz, M. E; Eermi, G.; Eogg, J.; Rahbar, S. J. Mol. Biol. 1988, 201, 459-461.

82. Tucker, P W; Perutz, M. E J. Mol. Biol. 1977, 114, 415-420.

83. Anderson, N. L.; Perutz, M. F Nat. New Biol. 1973, 243, 274-275.

85. Asakura, T; Adachi, K.; Wiley, J. S.; Fung, L. WC; Ho, C.; Kilmartin, J. V.; Perutz, M. F J. Mol. Biol. 1976, 104, 185-195.

86. Phillips, S. E.; Hall, D.; Perutz, M. F J. Mol. Biol. 1981, 150, 137-141.

87. Abraham, D. J.; Mehanna, A. S.; Williams, F L. J. Med. Chem. 1982, 25, 1015-1017.

88. Abraham, D. J.; Mokotoff, M.; Sheh, L.; Simmons, J. E. J. Med. Chem. 1983, 26, 549-554.

89. Abraham, D. J.; Perutz, M. F; Phillips, S. E. Proc. Natl. Acad. Sci. USA 1983, 80, 324-328.

90. Merrett, M.; Stammers, D. K.; White, R. D.; Wootton, R.; Kneen, G. Biochem. J. 1986, 239, 387-392.

91. Beddell, C. R.; Goodford, P. J.; Kneen, G.; White, R. D.; Wilkinson, S.; Wootton, R. Br. J. Pharmacol. 1984, 82, 397-407.

92. Keidan, A. J.; Franklin, I. M.; White, R. D.; Joy, M.; Huehns, E. R.; Stuart, J. Lancet 1986, 1, 831-834.

93. Fitzharris, P.; McLean, A. E.; Sparks, R. G.; Weatherley, B. C.; White, R. D.; Wootton, R. Br. J. Clin. Pharmacol. 1985, 19, 471-481.

94. Wireko, F C.; Abraham, D. J. Proc. Natl. Acad. Sci. USA 1991, 88, 2209-2211.

95. Padlan, E. A.; Love, W E. J. Biol. Chem. 1985, 260, 8272-8279.

96. Padlan, E. A.; Love, W E. J. Biol. Chem. 1985, 260, 8280-8291.

97. Wishner, B. C.; Ward, K. B.; Lattman, E. E.; Love, W E. J. Mol. Biol. 1975, 98, 179-194.

98. Cozzini, P; Fornabaio, M.; Marabotti, A.; Abraham, D. J.; Kellogg, G. E.; Mozzarelli, A. Curr. Med. Chem. 2004, 11, 3093-3118.

99. Abraham, D. J.; Mehanna, A. S.; Wireko, F C.; Whitney, J.; Thomas, R. P; Orringer, E. P Blood 1991, 77, 1334-1341.

100. Farthing, D.; Sica, D.; Abernathy, C.; Fakhry, I.; Roberts, J. D.; Abraham, D. J.; Swerdlow, P J. Chromatogr. B Biomed. Sci. Appl. 1999, 726, 303-307.

101. Abdulmalik, O.; Safo, M. K.; Chen, Q.; Yang, J.; Brugnara, C.; Ohene-Frempong, K.; Abraham, D. J.; Asakura, T Br. J. Haematol. 2005, 128, 552-561.

102. Safo, M. K.; Abdulmalik, O.; nso-Danquah, R.; Burnett, J. C.; Nokuri, S.; Joshi, G. S.; Musayev, F N.; Asakura, T; Abraham, D. J. J. Med. Chem.

2004, 47, 4665-4676.

103. Burnett, J. C.; Kellogg, G. E.; Abraham, D. J. Biochemistry 2000, 39, 1622-1633.

104. Cozzini, P; Fornabaio, M.; Marabotti, A.; Abraham, D. J.; Kellogg, G. E.; Mozzarelli, A. J. Med. Chem. 2002, 45, 2469-2483.

105. Fornabaio, M.; Spyrakis, F; Mozzarelli, A.; Cozzini, P.; Abraham, D. J.; Kellogg, G. E. J. Med. Chem. 2004, 47, 4507-4516.

106. Orringer, E. P; Blythe, D. S.; Whitney, J. A.; Brockenbrough, S.; Abraham, D. J. Am. J. Hematol. 1992, 39, 39-44.

107. Abraham, D. J.; Mehanna, A. S.; Williams, F S.; Cragoe, E. J., Jr.; Woltersdorf, O. W, Jr. J. Med. Chem. 1989, 32, 2460-2467.

108. Abraham, D. J.; Patwa, D. C. Clin. Chem. 1985, 31, 649-650.

109. Abraham, D. J.; Kennedy, P E.; Mehanna, A. S.; Patwa, D. C.; Williams, F L. J. Med. Chem. 1984, 27, 967-978.

110. Kennedy, P E.; Williams, F L.; Abraham, D. J. J. Med. Chem. 1984, 27, 103-105.

112. Richard, V; Dodson, G. G.; Mauguen, Y J. Mol. Biol. 1993, 233, 270-274.

113. Levine, B. D.; Stray-Gundersen, J. J. Appl. Physiol. 1997, 83, 102-112.

114. Arnaud, J.; Gutierrez, N. Am. J. Physiol. Anthropol. 2005, 63, 307-314.

115. Goodford, P. J.; St-Louis, J.; Wootton, R. Br. J. Pharmacol. 1980, 68, 741-748.

116. Beddell, C. R.; Goodford, P. J.; Stammers, D. K.; Wootton, R. Br. J. Pharmacol. 1979, 65, 535-543.

117. Goodford, P. J.; St-Louis, J.; Wootton, R. J. Physiol. 1978, 283, 397-407.

118. Goodford, P. J. Br. J. Pharmacol. 1978, 62, 428P-429P.

119. Goodford, P. J.; Norrington, F E.; Paterson, R. A.; Wootton, R. J. Physiol. 1977, 273, 631-645.

120. Brown, F F; Goodford, P J. Br. J. Pharmacol. 1977, 60, 337-341.

121. Beddell, C. R.; Goodford, P. J.; Norrington, F E.; Wilkinson, S.; Wootton, R. Br. J. Pharmacol. 1976, 57, 201-209.

122. Bedell, C. R.; Goodford, P. J.; Norrington, F E.; Wilkinson, S. Br. J. Pharmacol. 1973 , 48, 363P-364P

123. Abraham, D. J.; Wireko, F C.; Randad, R. S.; Poyart, C.; Kister, J.; Bohn, B.; Liard, J. F; Kunert, M. P. Biochemistry 1992, 31, 9141-9149.

124. Randad, R. S.; Mahran, M. A.; Mehanna, A. S.; Abraham, D. J. J. Med. Chem. 1991, 34, 752-757.

125. Safo, M. K.; Moure, C. M.; Burnett, J. C.; Joshi, G. S.; Abraham, D. J. Protein Sci. 2001, 10, 951-957.

126. Wireko, F C.; Kellogg, G. E.; Abraham, D. J. J. Med. Chem. 1991, 34, 758-767.

127. Suh, J. H.; Stea, B.; Nabid, A.; Kresl, J. J.; Fortin, A.; Mercier, J. P; Senzer, N.; Chang, E. L.;Boyd,A. P.; Cagnoni, P J. et al. J. Clin. Oncol. 2006, 24, 106-114.

128. Abraham, D. J.; Kister, J.; Joshi, G. S.; Marden, M. C.; Poyart, C. J. Mol. Biol. 1995, 248, 845-855.

129. Abraham, D. J. Drug Discovery in Academia - A Case Study. In Chemoinformatics in Drug Discovery; Oprea, T. I., Ed.; Wiley-VCH: Weinheim,

2005, pp 457-484.

130. Kilgore, K. S.; Shwartz, C. F; Gallagher, M. A.; Steffen, R. P; Mosca, R. S.; Bolling, S. F Circulation 1999, 100, II351-II356.

131. Paranka, N. Special Workshop Blood Doping in Sports and Detection Strategies: 7. Hemoglobin Modifiers; Is RRSR 13 the Next Aerobic Enhancer? ISLH XIVth International Symposium, 2006. http://www.tallonediachille.it/download/tesiGS.pdf (accessed Aug 2006).

132. Bauman, R. A.; Przybelski, R. J.; Bounds, M. J. Physiol. Behav. 1991, 50, 205-211.

133. Feola, M.; Simoni, J.; Canizaro, P C. Artif. Organs 1991, 15, 243-248.

134. Frantantoni, J. C. Transfusion 1991, 31, 369-371.

135. Walder, J. A.; Zaugg, R. H.; Walder, R. Y; Steele, J. M.; Klotz, I. M. Biochemistry 1979, 18, 4265-4270.

136. Chatterjee, R.; Welty, E. V; Walder, R. Y; Pruitt, S. L.; Rogers, P H.; Arnone, A.; Walder, J. A. J. Biol. Chem. 1986, 261, 9929-9937.

137. Snyder, S. R.; Welty, E. V; Walder, R. Y; Williams, L. A.; Walder, J. A. Proc. Natl. Acad. Sci. USA 1987, 84, 7280-7284.

138. Campanini, B.; Bruno, S.; Raboni, S.; Mozzarelli, A. Oxygen Delivery by Allosteric Effectors of Hemoglobin, Blood Substitutes, and Plasma Expanders. In Burger's Medicinal Chemistry and Drug Discovery; 6 th ed.; Abraham, D. J., Ed.; John Wiley: Hoboken, NJ, 2003; Vol. 1, pp 385-442.

139. Komiyama, N.; Tame, J.; Nagai, K. Biol. Chem. 1996, 377, 543-548.

140. Perutz, M. F; Fermi, G.; Abraham, D. J.; Poyart, C.; Bursaux, E. J. Am. Chem. Soc. 1986, 108, 1064-1978.

141. Abraham, D. J.; Safo, M. K.; Boyiri, T; Danso-Danquah, R. E.; Kister, J.; Poyart, C. Biochemistry 1995, 34, 15006-15020.

142. Schoenborn, B. P Nature 1965, 208, 760-762.

143. Mattevi, A.; Rizzi, M.; Bolognesi, M. Curr. Opin. Struct. Biol. 1996, 6, 824-829.

144. Matthews, D. A.; Bolin, J. T; Burridge, J. M.; Filman, D. J.; Volz, K. W; Kraut, J. J. Biol. Chem. 1985, 260, 392-399.

145. Kisliuk, R. L. Curr. Pharm. Des. 2003, 9, 2615-2625.

146. Appelt, K.; Bacquet, R. J.; Bartlett, C. A.; Booth, C. L.; Freer, S. T; Fuhry, M. A.; Gehring, M. R.; Herrmann, S. M.; Howland, E. F; Janson, C. A. J. Med. Chem. 1991, 34, 1925-1934.

147. Matthews, D. A.; Villafranca, J. E.; Janson, C. A.; Smith, W W; Welsh, K.; Freer, S. J. Mol. Biol. 1990, 214, 937-948.

148. Montfort, W R.; Perry, K. M.; Fauman, E. B.; Finer-Moore, J. S.; Maley, G. F; Hardy, L.; Maley, F; Stroud, R. M. Biochemistry 1990, 29, 6964-6977.

149. Takemura, Y; Jackman, A. L. Anticancer Drugs 1997, 8, 3-16.

150. Almog, R.; Waddling, C. A.; Maley, F; Maley, G. F; Van, R. P Protein Sci. 2001, 10, 988-996.

151. Jackson, S. Thumitaq completes enrollment in pivotal phase III liver cancer study, 4-19-2005. http://www.quakerbio.com/news/pcpr/2005/ Thymitaq%204.19.05.pdf (accessed Aug 2006).

152. Hardy, L. W; Safo, M. K.; Abraham, D. J. Structure-Based Drug Design. In Burger's Medicinal Chemistry and Drug Discovery; 6 th ed.; Abraham, D. J., Ed.; John Wiley: Hoboken, NJ, 2003; Vol. 1, pp 417-469.

153. Varney, M. D.; Marzoni, G. P.; Palmer, C. L.; Deal, J. G.; Webber, S.; Welsh, K. M.; Bacquet, R. J.; Bartlett, C. A.; Morse, C. A.; Booth, C. L. J. Med. Chem. 1992, 35, 663-676.

155. Norman, P Curr. Opin. Invest. Drugs 2001, 2, 1611-1622.

156. Taylor, E. C. Adv. Exp. Med. Biol. 1993, 338, 387-408.

157. Beardsley, G. P; Moroson, B. A.; Taylor, E. C.; Moran, R. G. J. Biol. Chem. 1989, 264, 328-333.

158. Piper, J. R.; McCaleb, G. S.; Montgomery, J. A.; Kisliuk, R. L.; Gaumont, Y; Thorndike, J.; Sirotnak, F M. J. Med. Chem. 1988, 31, 2164-2169.

159. Greasley, S. E.; Marsilje, T H.; Cai, H.; Baker, S.; Benkovic, S. J.; Boger, D. L.; Wilson, I. A. Biochemistry 2001, 40, 13538-13547.

160. Almassy, R. J.; Janson, C. A.; Kan, C. C.; Hostomska, Z. Proc. Natl. Acad. Sci. USA 1992, 89, 6114-6118.

161. Kan, C. C.; Gehring, M. R.; Nodes, B. R.; Janson, C. A.; Almassy, R. J.; Hostomska, Z. J. Protein Chem. 1992, 11, 467-473.

162. Varney, M. D.; Palmer, C. L.; Romines, W H., III; Boritzki, T; Margosiak, S. A.; Almassy, R.; Janson, C. A.; Bartlett, C.; Howland, E. J.; Ferre, R. J. Med. Chem. 1997, 40, 2502-2524.

163. Shih, C.; Gossett, L. S.; Worzalla, J. F; Rinzel, S. M.; Grindey, G. B.; Harrington, P M.; Taylor, E. C. J. Med. Chem. 1992, 35, 1109-1116.

164. Bissett, D.; McLeod, H. L.; Sheedy, B.; Collier, M.; Pithavala, Y; Paradiso, L.; Pitsiladis, M.; Cassidy, J. Br. J. Cancer 2001, 84, 308-312.

165. Tzakos, A. G.; Gerothanassis, I. P ChemBioChem 2005, 6, 1089-1103.

166. Varney, M. D. Copy of the presentation that he made in 1998 to a medicinal chemistry symposium concerning the lessons learned in ten years of using SBDD methods. Abraham, D. J. 2003. Ref Type: Personal Communication: June 13-19, 1998; 26th National Medicinal Chemistry Symposium; Richmond, USA.

167. Perutz, M. F I Wish I Would Have Made You Angrier Earlier: Essays on Science, Scientists, and Humanity; Cold Spring Harbor Laboratory Press: Plainview, NY, 1998, p X.

168. Hartshorn, M. J.; Murray, C. W; Cleasby, A.; Frederickson, M.; Tickle, I. J.; Jhoti, H. J. Med. Chem. 2004, 48, 403-413.

169. Overview of Focus Area 1: Enhance Biotechnology through Research and Innovation to Expand Biotechnology-related Businesses and the Kentucky Economy, 2006. http://www.rgs.uky.edu/area1.pdf (accessed Aug 2006).

171. Campbell, S. F Clin. Sci. (Lond.) 2000, 99, 255-260.

172. Kubinyi, H. Nat. Rev. Drug Disc. 2003, 2, 665-668.

173. The New Jersey Initiative in Structural Genomics and Bioinformatics (NJISGB), Connecting Gene Sequence to Function by 3D Structure Determination - A New Paradigm for Drug Discovery, 1999. http://www-nmr.cabm.rutgers.edu/structuralgenomics/concept.html (accessed Aug 2006).

174. The Australian Government's Vision for Australian Biotechnology, 2002. http://www.biotechnology.gov.au/assets/documents/bainternet/ BA%5FBiotech%5Fstrategy20050520161600%2Epdf (accessed Aug 2006).

175. Overview of Focus Area 1: Enhance Biotechnology through Research and Innovation to Expand Biotechnology-Related Businesses and the Kentucky Economy, 2006. http://www.rgs.uky.edu/area1.pdf (accessed Aug 2006).

176. Acharya, T; Daar, A. S.; Thorsteinsdöttir, H.; Dowdeswell, E.; Singer, P A. PLoS Medicine 2004,1, 40; Genomics and Global Health: A report of the genomics working group of the ience and technology task force of the United Nations Millennium Project, 2004. http:// www.medicine.plosjournals.org/perlservFrequest = get-document&doi = 10.1371/journal.pmed.0010040 (accessed Aug 2006).

177. Ringe, D.; Petsko, G. A. Methods Enzymol. 1986, 131, 389-433.

178. Hajdu, J.; Machin, P A.; Campbell, J. W; Greenhough, T J.; Clifton, I. J.; Zurek, S.; Gover, S.; Johnson, L. N.; Elder, M. Nature 1987, 329, 178-181.

179. Schotte, F; Soman, J.; Olson, J. S.; Wulff, M.; Anfinrud, PA. J. Struct. Biol. 2004, 147, 235-246.

180. Henderson, R. Q. Rev Biophys. 1995, 28, 171-193.

181. Kisseberth, N.; Whittaker, M.; Weber, D.; Potter, C. S.; Carragher, B. J. Struct. Biol. 1997, 120, 309-319.

182. Hadida-Hassan, M.; Young, S. J.; Peltier, S. T; Wong, M.; Lamont, S.; Ellisman, M. H. J. Struct. Biol. 1999, 125, 235-245.

183. Baumeister, W; Grimm, R.; Walz, J. Trends Cell Biol. 1999, 9, 81-85.

184. McEwen, B. F; Downing, K. H.; Glaeser, R. M. Ultramicroscopy 1995, 60, 357-373.

Biography

Donald J Abraham is Professor and Chair of the Department of Medicinal Chemistry at Virginia Commonwealth University and is the Director of the Institute for Structural Biology and Drug Discovery. He holds a BS degree in chemistry from Pennsylvania State University, an MS in organic chemistry from Marshall University, and a PhD in organic chemistry from Purdue University. Dr Abraham's research is interdisciplinary and focuses on structure-based drug design including x-ray crystallography, molecular modeling, synthetic medicinal chemistry, and structural function studies involving allosteric proteins. Targeted therapeutic areas of research include sickle cell anemia, radiation oncology, ischemic cardiovascular diseases, stroke, cancer, and Alzheimer's disease.

© 2007 Elsevier Ltd. All Rights Reserved Comprehensive Medicinal Chemistry II

No part of this publication may be reproduced, stored in any retrieval system or transmitted ISBN (set): 0-08-044513-6 in any form by any means electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publishers ISBN (Volume 4) 0-08-044517-9; pp. 65-86

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