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Hugo Kubinyi, www.kubinyi.de
Ligand-ProteinInteractions
Hugo Kubinyi
Germany
E-Mail [email protected] www.kubinyi.de
Hugo Kubinyi, www.kubinyi.de
Lucretius, about 50 B.C.De Rerum Natura, Book II, Section “Atomic Formsand Their Combinations”
We see how quickly through a colander The wines will flow; how, on the other hand, The sluggish olive-oil delays: no doubt, Because 'tis wrought of elements more large, Or else more crook'd and intertangled.
HO
H
OH
O
O
O
O
O
O
Hugo Kubinyi, www.kubinyi.de
The book “Chemische Studien“(Chemical Studies), Vienna, 1861, ofthe Austrian school teacher JosephLoschmidt contains aready structuresthat are formulated like the benzenering (Kekulé, 1865) and like today‘smolecular modelling pictures.August Kekulé knew this book latestin 1862.
„Wir nehmen für den Kern das Symbol Sch. 184 an, und behandeln denselben ganz so, als ob er ein sechsstelliges Element wäre.“(J. Loschmidt in „Chemische Studien“, 1861, p. 30)
Hugo Kubinyi, www.kubinyi.de
H
HOH
O
NH2 NH2
N N
NN
N
Cl
HH
Loschmidt Constitution Formulas (1861)
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The Benzene Formula of August Kekulé (1865)
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Benzene
„Reports of the Thirsty Chemical Society“ (Berichte der Durstigen Chemischen Gesellschaft), 1886
cited from E. Bäumler, Ein Jahrhundert Chemie, Econ Verlag Düsseldorf, 1963, p. 20
Hugo Kubinyi, www.kubinyi.de
The Arrangement of Atoms in Space - van‘t Hoff, 1874-77
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Models of Different Tetrahedric Carbons
van‘tHoff
(1904)
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Molecular Models of d- and l-Carvone
Hugo Kubinyi, www.kubinyi.de
Molecular Model of Dopamine
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„Ball and Stick“ Model of Dopamine
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„Dotted Surface“ Model of Dopamine
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„Space-Filling“ (CPK) Model of Dopamine
Hugo Kubinyi, www.kubinyi.de
„Colour-Coded Surface“ Model of Dopamine
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Molecular Electrostatic Potential of Dopamine
Hugo Kubinyi, www.kubinyi.de
Dopamine, HOMO and LUMO Potentials
Hugo Kubinyi, www.kubinyi.de
Molecular Modelling of a Host-Guest ComplexBenzene in a Macrocyclic Ring System
Hugo Kubinyi, www.kubinyi.de
Lock and Key Concept (Emil Fischer, 1894)
“To use a picture, I would like to say that enzyme and glucoside have to fit like a lock and a key, in order to exert a chemical action on each other”.
Hugo Kubinyi, www.kubinyi.de
Toxins and „Receptors“ (Paul Ehrlich, around 1900)
Hugo Kubinyi, www.kubinyi.de
Paul Ehrlich (1854-1915)
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Henry MooreTwo Forms
Pynkado wood, 1934
MetropolitanMuseum of Art,New York
© MMA, N.Y.
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S
O
NO
NOH
NHN
OO
N
O
HH
H
CGP-38560,a Renin Inhibitor
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Which onesare the fittingkeys ?
How todifferentiate ?
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Peter AndrewsDiagram
Enthalpic and EntropicContributionsto LigandAffinity
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Protein Ligand
Hydrogenbonds
("salt bridge")
Hydrophobic interactions
Cation-ππππ interaction
Ionic interactions
O
O H
CH3
H N
O
CH3
H3N
N+
N
NHH
HH
Metall ion complexZn2+
SH
+
O
O-
O
O-
+
Important Non-Covalent Ligand-Protein Interactions
The inhibition constant Ki is a measure of the strength of the ligand-protein interaction
∆∆∆∆G = ∆∆∆∆H - T∆∆∆∆S = RT ln Ki
Hugo Kubinyi, www.kubinyi.de
3D Structures, Superposition of Molecules and Pharmacophore HypothesesExperimental determination of 3D structures:
X-ray structure analysis, 2D NMRGeneration of 3D Structures
Concord, CORINA (rule-based systems)Force field and QC methods
Multiple 3D structuresSystematic and Monte-Carlo search, moleculardynamics simulation, rule-based systems
Superposition of molecules„rigid fit“, „field fit“ (SEAL)
Pharmacophore hypotheses„Active analog approach“, 3- and 4-pointpharmacophores, CATALYST
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3D-Structures: Conformational Analysis
torsion angle, in degrees
energy in kJ
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2D-3D Conversion and Conformational Analysis
- Conformations are local energy minima of a molecule- Generate a start structure- Sample the conformational space MD, MC, GA, rule-based approaches- Minimize structure if necessary
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The Relevance of Different Conformations
a) in vacuo b) in water c) in the crystal
Citric Acid
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Binding Mode of Citric Acid in Citrate Synthase
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Cyclosporin A
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Molecular Mechanics - Force Fields
E
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E = Krbond∑ r − r0( )2
+ Kθangl∑ θ − θ0( )2
+ Kφdihed∑ 1+ cos nφ− γ( )[ ]
+Aij
rij12 −
Bij
rij6 +
qiq j
εrij
ij∑
Force Field Terms
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Preferred Torsion Angles in Phe-X-Phe
diphenyl-methane (X = CH2)
diphenyl ether (X = O)
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TorsionAnglePatterns
(from CCD)
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N
NN
N
NH2
O
OHOH
O
P
OOHO
ττττ1
ττττ3 ττττ2
ττττ4444
- Conformer Population ofNucleotides (from PDB)
Hugo Kubinyi, www.kubinyi.de
[%] [%]
010203040
0 30 60 90 120 150 180 210 240 270 300 330 3600
20
40
60
0 30 60 90 120 150 180 210 240 270 300 330 360
Torsion Angle [°] Torsion Angle [°]
N
NN
N
NH2
O
OO
OPO
O
O
τ 1
τ 3 τ 2
τ 4444
-
[%] [%]
0
20
40
60
0 30 60 90 120 150 180 210 240 270 300 330 360
0
5
10
15
0 30 60 90 120 150 180 210 240 270 300 330 360
Torsion Angle [°] Torsion Angle [°]
Torsion anglestatistics from the CambridgeCrystallographicDatabase
Rule-basedSystem forthe Prediction of Multiple3D-Structures
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Superposition of Molecules: Alignment by SEAL
Hugo Kubinyi, www.kubinyi.de
GRID Molecular Interactions Fields
Peter Goodford, 1984; R. C. Wade, in 3D QSAR in Drug Design, H. Kubinyi, Ed., ESCOM, 1993, pp. 486-505
• GRID calculates interaction energies between atomic probes or functional groups and a ligand or a protein at equally distributed grid points.
• Considers force field parameters like van-der-Waals and electrostatic interactions.
• Contains basic concepts to include side chain flexibility.
• Used for CoMFA and docking.
Hugo Kubinyi, www.kubinyi.de
GRID Molecular Interaction Fields (P. Goodford)
GRID molecular interaction fields of nifedipinea) hydroxy probe (left; contour map at –3.5 kcal mol-1) andb) methyl probe (right; contour map at –1.4 kcal mol-1).
Hugo Kubinyi, www.kubinyi.de
Superpositionof ThrombinInhibitors
(coordinatesfrom X-raystructureanalyses ofthe inhibitorcomplexes)
Hugo Kubinyi, www.kubinyi.de
O
O N
N
S
OO O
N
O
N
O
O
Br
Molecular Superposition of D Receptor Ligands
+
+
S
N
NHMe
Me
OH
NH
HN MeOH
Br
NHH
OHOH
Me
+
+
