Milestones in Crystallography and Drug Design Jenny P. Glusker Fox Chase Cancer Center Philadelphia, PA 19111 USA 1. Determination of molecular structures by X-ray diffraction of crystals 2. Development of user-friendly computers 3. Their convergence to DRUG DESIGN
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Milestones in Crystallography and Drug Design Jenny P. Glusker Fox Chase Cancer Center Philadelphia, PA 19111 USA 1. Determination of molecular structures.
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Milestones in Crystallography and Drug Design
Jenny P. GluskerFox Chase Cancer CenterPhiladelphia, PA 19111 USA
1. Determination of molecular structures by X-ray diffraction of crystals
2. Development of user-friendly computers
3. Their convergence to DRUG DESIGN
Seeing moleculesElectron microscopy X-ray diffraction of crystals
Early milestones in structure analysis
1. Discovery of X rays1895 Wilhelm Conrad RöntgenNobel Prize (physics) 1901Nature 53, 274 (1896)
2. Diffraction of X rays1912 Max Theodor Felix von LaueNobel Prize (physics) 1914Sitzungsber. Bayer. Akad. Wiss. Munchen p. 303 (1912)
3. Structure determination1913 William Henry Bragg & William Lawrence BraggNobel Prize (physics) 1915Proc. Roy. Soc. A89, 248 (1913)
A substrate analoguedoes not always bindin the same way as the substrate
1977
Science 197, 452 (1977)
Transition states
Linus Pauling, C&E News 24, 1375 (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
1946
Intermolecular interactions
Rosenfield JACS 99 4860 (1977)
1977
Intermolecular interactions
Murray-RustJACS 106, 1018 (1984)
1984
DNA interactions
SeemanPNAS 73, 804 (1976)
1976
Following reactionsBurgi, Dunitz, Shefter
Burgi, DunitzShefter JACS 95, 5065 (1973)
1973
Following reactionsLaue method
(Nature 329, 178 (1987)
1
3 4
2
1987
Homology modeling -secretaseWild-type beta secretase Swedish mutant