Milestones in Crystallography and Drug Design

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 19111 USA

2. Seeing molecules Electronmicroscopy 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. 303 (1912) 3. Structure determination 1913 William Henry Bragg & William Lawrence Bragg Nobel Prize (physics) 1915 Proc. Roy. Soc. A89, 248 (1913)

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

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

6. 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. 1913 Sodium chloride structure W. L. Bragg. Proc. Roy. Soc. A89, 248 (1913)

9. 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. 1930 Patterson functionpotassium dihydrogen phosphate

14. 1931 1931

15. 1931

16. 1934

17. 1936

18. 1930

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

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

21. 1951 Absolute configurationJ. M. Bijvoet

22. 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. 1955 Morphine MORPHI Mackay & Hodgkin J.Chem. Soc. 3261 (1955) MORPHM Bye Acta Chem. Scand. B30, 549 (1976)

25. 1960 Computing of the time 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. 1928 Hexamethylbenzene 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. 1966 Lysozyme with polysaccharide Sci. Amer. 215, 75 (1966)

35. 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. 1977 Intermolecular interactions Rosenfield JACS 99 4860 (1977)

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

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

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

41. 1987 Following reactionsLaue method (Nature 329, 178 (1987) 1 2 3 4

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