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

Seeing molecules Electron microscopy X-ray diffraction of crystals

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)

Early X-ray photograph (Röntgen, 1895)

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

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

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

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

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

Electron-density maps and phases

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

1930

Patterson function potassium dihydrogen phosphate 1930 Patterson function potassium dihydrogen phosphate

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

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

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

Penicillin chemical formula 1949 Penicillin chemical formula b-lactam oxazolone

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

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

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

Direct methods

Electron-density maps and phases

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

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

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

1953 B DNA fibers

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

1985 Cytochrome P450 Biochem. 26, 8165 (1987)

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

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

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)

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

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

1976 DNA interactions Seeman PNAS 73, 804 (1976)

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

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

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