Penicillin from 1FXV

Penicillin from 1FXV

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 Rntgen 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) 1895 Early X-ray photograph (Rntgen, 1895)

Diffraction by a sieve and a crystalline virus 1958 photograph of a point source of light taken through a sieve tobacco necrosis virus crystal

courtesy R.W.G. Wyckoff 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

1913 Sodium chloride structure W. L. Bragg. Proc. Roy. Soc. A89, 248 (1913) 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 1930 Patterson function potassium dihydrogen phosphate 1931

1931 1931 1934 1936 1930

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

HO Wieland, Dane formula (also crystal structure) 1951

Absolute configuration J.M. Bijvoet Nature 168, 271 (1951) 1951 Absolute configuration J. M. Bijvoet 1949

Penicillin chemical formula HOOC HOOC H CH3 CH3

N H CH3 HN S

S O H H NH

O CH3 O N O CH2 Ph

-lactam CH2 Ph oxazolone Penicillin

Penicillin G in penicillin acylase 1FXV Protein Eng. 13, 857 (2000) and 1GM7 J. Mol. Biol. 313, 139 (2001) 1955 Morphine HO CH3

N O H HO morphine MORPHI Mackay & Hodgkin J.Chem. Soc. 3261 (1955) MORPHM Bye Acta Chem. Scand. B30, 549 (1976)

1960 Computing of the time Cambridge EDSAC 2 Computer 1960 Cosine function,

Beevers-Lipson strip and IBM punched card Patterson projection of whale myoglobin

Direct methods Electron-density maps and phases 1928 Hexamethylbenzene

h k l 7 -3 0 340 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)

1966 Lysozyme with polysaccharide Sci. Amer. 215, 75 (1966) 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) 1977 Intermolecular interactions

Rosenfield JACS 99 4860 (1977) 1984 Intermolecular interactions Murray-Rust JACS 106,

1018 (1984) 1976 DNA interactions Seeman PNAS 73, 804 (1976)

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

Following reactions Laue method (Nature 329, 178 (1987) 1 2

3 4 1987 2000 Homology modeling -secretase

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

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