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)

Early X-ray photograph(Röntgen, 1895)

1895

Diffraction by a sieve anda crystalline virus

tobacco necrosis virus crystalcourtesy R.W.G. Wyckoff

photograph of a point sourceof light taken through a sieve

1958

The first X-ray diffraction photographs of crystals

(Friedrich and Knipping, 1912)

1912

Apparatus for X-ray diffraction

detectionsystem

crystal

source ofX rays

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

1913

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 amplitudesof electron-density waves and can lead toatomic positions if the PHASE PROBLEMcan be solved

1930

Patterson functionpotassium dihydrogen phosphate

1930

19311931

1931

1934

1936

1930

Steroid structure (Bernal)

Wieland and Windaus formulae

Bernal, RosenheimKing formula

Wieland, Daneformula(also crystal structure)

HO

1932

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

1951

Absolute configurationJ. M. Bijvoet

1951

Penicillin chemical formula

S

N

HOOCCH3

CH3

O

NH

CH2Ph

O

H

H

S

HN

HOOC

CH3

CH3

N

O

O

CH2Ph

H

H

1949

-lactam oxazolone

Penicillin

Penicillin G in penicillin acylase 1FXV Protein Eng. 13, 857 (2000) and1GM7 J. Mol. Biol. 313, 139 (2001)

Morphine

HO

O

HO

H

N

CH3

morphine

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

1955

Computing of the time

Cambridge EDSAC 2Computer 1960

1960

Cosine function,Beevers-Lipson strip and IBMpunched card

Patterson projection of whalemyoglobin

Direct methods

Electron-density maps and phases

Hexamethylbenzene

K. Lonsdale. Nature 122, 810 (1928)

h k l7 -3 0 3 4 04 -7 0 intense(triplet)

1928

Vitamin B12 coenzyme structure

Hodgkin. Nature 176, 325 (1955),

Vitamin B12 coenzyme

1955

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

B DNA fibers

1953

Myoglobin

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

1960

Cytochrome P450

1985

Biochem. 26,8165 (1987)

Lysozyme with polysaccharide

1966

Sci. Amer. 215, 75 (1966)

Dihydrofolate reductase

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

(better substrate)

Dunbrack, J. Mol. Biol. 300, 241 (2000)

2000