Milestones in Crystallography and Drug Design

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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
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Seeing molecules
Electron microscopy X-ray diffraction of
crystals
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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)
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Early X-ray photograph(Röntgen, 1895)
1895
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Diffraction by a sieve anda crystalline virus
1958
photograph of a point source of light taken
through a sieve
tobacco necrosis virus crystal courtesy R.W.G.
Wyckoff
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The first X-ray diffraction photographs of
crystals
1912
(Friedrich and Knipping, 1912)
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Apparatus for X-ray diffraction
crystal
detection system
source of X rays
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Sodium chloride structure
1913
W. L. Bragg. Proc. Roy. Soc. A89, 248 (1913)
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Sodium and potassium chlorides
1913
KCl
NaCl
KCl has larger unit cell than NaCl, therefore
diffraction lines are closer for KCl
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Electron-density maps and phases
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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
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1930
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Patterson functionpotassium dihydrogen phosphate
1930
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1931
1931
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1931
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1934
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1936
18
1930
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Steroid structure (Bernal)
1932
Wieland and Windaus formulae
Bernal, Rosenheim King formula Wieland,
Dane formula (also crystal structure)
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Absolute configuration J.M. Bijvoet Nature 168,
271 (1951)
1951
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Absolute configurationJ. M. Bijvoet
1951
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Penicillin chemical formula
1949
b-lactam oxazolone
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Penicillin
Penicillin G in penicillin acylase 1FXV Protein
Eng. 13, 857 (2000) and 1GM7 J. Mol. Biol. 313,
139 (2001)
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Morphine
1955
MORPHI Mackay Hodgkin J.Chem. Soc. 3261
(1955) MORPHM Bye Acta Chem. Scand. B30, 549
(1976)
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Computing of the time
1960
Cosine function, Beevers-Lipson strip and
IBM punched card
Patterson projection of whale myoglobin
Cambridge EDSAC 2 Computer 1960
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Direct methods
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Electron-density maps and phases
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Hexamethylbenzene
1928
h k l 7 -3 0 3 4 0 4 -7 0 intense (triplet)
K. Lonsdale. Nature 122, 810 (1928)
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Vitamin B12 coenzyme structure
Hodgkin. Nature 176, 325 (1955),
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Vitamin B12 coenzyme
1955
Hodgkin. Nature 176, 325 (1955), Proc. Roy. Soc.
A303, 45 (1968)
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B DNA fibers
1953
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Myoglobin
1960
Kendrew and co-workers Nature 185, 422 (1960)
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Cytochrome P450
1985
Biochem. 26, 8165 (1987)
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Lysozyme with polysaccharide
1966
Sci. Amer. 215, 75 (1966)
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Dihydrofolate reductase
1977
A substrate analogue does not always bind in the
same way as the substrate
Science 197, 452 (1977)
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Transition states
1946
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, CE News 24, 1375 (1946)
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Intermolecular interactions
1977
Rosenfield JACS 99 4860 (1977)
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Intermolecular interactions
1984
Murray-Rust JACS 106, 1018 (1984)
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DNA interactions
1976
Seeman PNAS 73, 804 (1976)
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Following reactionsBurgi, Dunitz, Shefter
1973
Burgi, Dunitz Shefter JACS 95, 5065 (1973)
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Following reactionsLaue method (Nature 329, 178
(1987)
1987
1
2
3
4
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Homology modeling b-secretase
2000
Wild-type beta secretase Swedish
mutant (better substrate)
Dunbrack, J. Mol. Biol. 300, 241 (2000)