1. Milestones in Crystallography and Drug Design
1. Determination of molecular structures
by X-ray diffraction of crystals
2. Development of user-friendly computers
3. Their convergence to DRUG DESIGN
Jenny P. Glusker
Fox Chase Cancer Center
Philadelphia, PA USA

2. Seeing molecules
Electron microscopy X-ray diffraction of crystals

3. Early milestones in structure analysis
1. Discovery of X rays
1895 Wilhelm Conrad Röntgen
Nobel Prize (physics) 1901
Nature 53, 274 (1896)
2. Diffraction of X rays
1912 Max Theodor Felix von Laue
Nobel Prize (physics) 1914
Sitzungsber. Bayer. Akad. Wiss. Munchen p (1912)
3. Structure determination
1913 William Henry Bragg & William Lawrence Bragg
Nobel Prize (physics) 1915
Proc. Roy. Soc. A89, 248 (1913)

4. Early X-ray photograph (Röntgen, 1895)

5. Diffraction by a sieve and a crystalline virus
1958
Diffraction by a sieve and a crystalline virus
photograph of a point source
of light taken through a sieve
tobacco necrosis virus crystal
courtesy R.W.G. Wyckoff

6. The first X-ray diffraction photographs of crystals
1912
The first X-ray diffraction photographs of crystals
(Friedrich and Knipping, 1912)

7. Apparatus for X-ray diffraction
crystal
detection
system
source of
X rays

8. Sodium chloride structure
1913
Sodium chloride structure
W. L. Bragg. Proc. Roy. Soc. A89, 248 (1913)

9. Sodium and potassium chlorides
1913
Sodium and potassium chlorides
KCl
NaCl
KCl has larger unit cell than NaCl, therefore diffraction lines are closer for KCl

10. Electron-density maps and phases

11. Information from X-ray diffraction
1. Angles of diffracted beams give the unit-cell
dimensions
2. Orders of diffraction (h,k,l) give the periodicities
of the electron-density waves
3. Intensities of diffracted beams give amplitudes
of electron-density waves and can lead to
atomic positions if the PHASE PROBLEM
can be solved

12. 1930

13. Patterson function potassium dihydrogen phosphate
1930
Patterson function potassium dihydrogen phosphate

14. 1931
1931

15. 1931

16. 1934

17. 1936

18. 1930

19. Steroid structure (Bernal)
1932
Steroid structure (Bernal)
Wieland and Windaus
formulae
Bernal, Rosenheim
King formula
Wieland, Dane
formula
(also crystal structure)

20. Absolute configuration J.M. Bijvoet Nature 168, 271 (1951)

21. Absolute configuration J. M. Bijvoet
1951
Absolute configuration J. M. Bijvoet

22. Penicillin chemical formula
1949
Penicillin chemical formula
b-lactam oxazolone

23. Penicillin Penicillin G in penicillin acylase
1FXV Protein Eng. 13, 857 (2000) and
1GM7 J. Mol. Biol. 313, 139 (2001)

24. Morphine 1955 MORPHI Mackay & Hodgkin J.Chem. Soc. 3261 (1955)
MORPHM Bye Acta Chem. Scand. B30, 549 (1976)

25. Computing of the time 1960 Cosine function, Beevers-Lipson
strip and IBM
punched card
Patterson
projection
of whale
myoglobin
Cambridge EDSAC 2
Computer 1960

26. Direct methods

27. Electron-density maps and phases

28. Hexamethylbenzene 1928 h k l 7 -3 0 3 4 0 4 -7 0 intense (triplet)
K. Lonsdale. Nature 122, 810 (1928)

29. Vitamin B12 coenzyme structure
Hodgkin. Nature 176, 325 (1955),

30. 1955
Vitamin B12 coenzyme
Hodgkin. Nature 176, 325 (1955), Proc. Roy. Soc. A303, 45 (1968)

31. 1953
B DNA fibers

32. 1960
Myoglobin
Kendrew and co-workers Nature 185, 422 (1960)

33. 1985
Cytochrome P450
Biochem. 26,
8165 (1987)

34. Lysozyme with polysaccharide
1966
Lysozyme with polysaccharide
Sci. Amer. 215, 75 (1966)

35. Dihydrofolate reductase
1977
Dihydrofolate reductase
A substrate analogue
does not always bind
in the same way as the
substrate
Science 197, 452 (1977)

36. 1946
Transition states
A enzyme lowers the energy barriers of a reaction
by preferentially stabilizing the transition state of
the substrate during the reaction rather than the
ground state of that substrate
Linus Pauling, C&E News 24, 1375 (1946)

37. Intermolecular interactions
1977
Intermolecular interactions
Rosenfield JACS (1977)

38. Intermolecular interactions
1984
Intermolecular interactions
Murray-Rust
JACS 106,
1018 (1984)

39. 1976
DNA interactions
Seeman
PNAS 73,
804 (1976)

40. Following reactions Burgi, Dunitz, Shefter
1973
Following reactions Burgi, Dunitz, Shefter
Burgi, Dunitz
Shefter JACS
95, 5065 (1973)

41. Following reactions Laue method (Nature 329, 178 (1987)4

42. Homology modeling b-secretase
2000
Homology modeling b-secretase
Wild-type beta secretase Swedish mutant
(better substrate)
Dunbrack, J. Mol. Biol. 300, 241 (2000)