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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
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)
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
The first X-ray diffraction
photographs of crystals
(Friedrich and Knipping, 1912)
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)
Absolute configuration
J.M. Bijvoet Nature 168, 271 (1951)
1951
1951
Absolute configuration
J. M. Bijvoet
1949
Penicillin chemical formula
HOOC
HOOC
H
H
CH3
CH3
N
CH3
HN
S
S
O
CH3
H
H
O
NH
O
N
O
CH2 Ph
b-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 b-secretase
Wild-type beta secretase
Swedish mutant
(better substrate)
Dunbrack, J. Mol. Biol. 300, 241 (2000)