Download - 3D Database Searching and Scaffold Hopping
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M. Wagener
3D Database Searching and 3D Database Searching and Scaffold HoppingScaffold Hopping
Markus Wagener
NV Organon
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M. Wagener
Database SearchingDatabase Searching
• Selection of compounds for testing
• Generation of new ideas
• Validation of proposed structural requirements for activity
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M. Wagener
Lock-and-Key PrincipleLock-and-Key Principle
‘‘. . . the intimate contact between the molecules . . . is possible only with similar geometrical configurations. To use a picture, I would say that the enzyme and the substrate must fit together like a lock and key.’’
Emil Fischer, Ber. Dtsch. Chem. Ges. 1894, 27, 2985.
Receptor
Ligand
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M. Wagener
3D Database Searching3D Database Searching
Docking
Using the lock, find keys that fit
Pharmacophore Search
Look for keys with same features
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M. Wagener
OutlineOutline
• Database Building– 2D-to-3D Conversion– Multi-Conformational Databases
• Pharmacophoric Searches
• Scaffold Databases
• Scaffold Hopping
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M. Wagener
Available Compound CollectionsAvailable Compound Collections
0
50
100
150
200
250
300
350
400
in house ACD WDI NCI Maybridge Specs
Siz
e x
100
0
http://cactus.nci.nih.gov/ncidb2/
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M. Wagener
2D-to-3D Conversion: Corina2D-to-3D Conversion: Corina
OH
NH
NH
SO
OH
J. Sadowski, J. Gasteiger Chem. Rev. 1993, 93, 2567.
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M. Wagener
Fragmentation into Cyclic/Acyclic Parts Fragmentation into Cyclic/Acyclic Parts
OH
NH
NH
SO
OH
NH
SO
O
N
S
NH
OH
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M. Wagener
Ring TemplatesRing Templates
27 kJ/Mol
50 kJ/Mol
56 kJ/Mol
18 kJ/Mol
25 kJ/Mol
43 kJ/Mol
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M. Wagener
Joining of Ring Templates: CubaneJoining of Ring Templates: Cubane
Ring 2 Ring 3 Ring 4 Ring 5
no conformationfor 3rd ring
Ring 1
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M. Wagener
Joining the FragmentsJoining the Fragments
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M. Wagener
Conformational FlexibilityConformational Flexibility
conformationalensemble
low-energyconformation
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M. Wagener
Conformational AnalysisConformational Analysis
• Systematic Search
– high number of conformers:
e.g. 10 rotatable bonds with 120º steps: 310 ~ 60,000
conformers
• Sampling Techniques
– Molecular Dynamics, Distance Geometry, Simulated
Annealing
• Poling: Promoting Conformational Variation
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M. Wagener
Conformational FlexibilityConformational Flexibility
0
5
10
15
20
25
30
0 60 120 180 240 300 360
Ene
rgy
[kJ/
Mol
]
Torsion Angle
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M. Wagener
Conformational PolingConformational Poling
A. Smellie, S.L. Teig, P. Towbin J. Comp. Chem. 1995, 16, 171.
Conformational Coordinate
Ene
rgy
+ Epole
Energy =
Ebond
+ Eangle
+ Edihedral
+ Enonbonding
C3 C2
C1
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M. Wagener
Lock-and-Key PrincipleLock-and-Key Principle
‘‘. . . the intimate contact between the molecules . . . is possible only with similar geometrical configurations. To use a picture, I would say that the enzyme and the substrate must fit together like a lock and key.’’
Emil Fischer, 1891
Receptor
Ligand
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M. Wagener
Protein-Ligand InteractionProtein-Ligand Interaction
O
OH
H3N+O
O
• hydrogen bonds• salt bridges• hydrophobe
interactions• cation-π interactions• metal complexes
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M. Wagener
Pharmacophore DefinitionPharmacophore Definition
A pharmacophore is a specific spatial arrangement of atoms or functional groups required for a drug molecule to exert a particular biological effect.
OH
OHNH
OH
adrenaline
2 - 3 Å
4 - 7.2 Å
6 - 8 Å
adapted from: C.D. Strader et al. J. Biol. Chem. 1989, 264, 13572.
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M. Wagener
Pharmacophore ElementsPharmacophore Elements
Hydrogen bond donors:
Hydrogen bond acceptors:
Hydrophobes:
Positive ionizable groups:
Negative ionizable groups:O
O
N+
H
N
H
N
O
H
O
H
O
N
O
H
N N+
H
H
H
H
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M. Wagener
Pharmacophore SearchingPharmacophore Searching
2 - 3 Å
4 - 7.2 Å
6 - 8 Å
3DDatabase
14251druglike compounds
843search hits
7 CPU min
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M. Wagener
Alignment of 2 Search Hits Alignment of 2 Search Hits
OH
NH
NH
SO
OH
OH
OHNH
OH
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M. Wagener
Quality of the PharmacophoreQuality of the Pharmacophore
• Adrenergic agonists:
Hitsactive / Hitstotal
DBactive / DBtotal
EF = = 7.049 / 843
119 / 14251=
Hitsactive / Hitstotal
DBactive / DBtotal
EF = = 4.341 / 843
162 / 14251=
• Dopaminic Agonists:
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M. Wagener
O
N
O
OH
OH
New Scaffold
O
N
O
OH
OH
SOH
OH
O
O
N
SOH
OH
O
O
N
Scaffold HoppingScaffold Hopping
Breaking out of old series:
• no further optimization possible
• patent issues
• backup
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M. Wagener
O
O
F
O
Conventional ApproachesConventional Approaches
Similarity Search
uses overall similarity to retrieve structures
Pharmacophore Search
focuses on features important for receptor-ligand
interaction
SOH
OH
O
O
N
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M. Wagener
Scaffold HoppingScaffold Hopping
Goal
Find similar scaffolds, not similar compounds
Approach
1) Generate a non-redundant database of scaffolds
2) Store position and orientation of substitution
sites
3) Use orientation of substitution sites on the query
to identify new scaffolds
Example
Estrogen antagonists
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M. Wagener
Generating the Scaffolds DatabaseGenerating the Scaffolds Database
ACD
Organon
Drugs
Scaffolds
scaffoldextraction
canonization
conformational
analysis
R
R
O
R
R
R
N
R
R
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M. Wagener
Scaffold ExtractionScaffold Extraction
SR
R
R
SR
R
O
R
SR
R
R
SOH
OH
O
O
N
ringsystem
scaffold
π-scaffold
R R
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M. Wagener
Searching the DatabaseSearching the Database
3D query
Scaffolds
suggestedscaffolds
N
R
R
R
R
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M. Wagener
raloxifene
substitution sites
+ aromatic ring
+ ring orientation
+ directions
3D query
+ shape
A Query for ER antagonistsA Query for ER antagonists
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M. Wagener
Hits with the ER Antagonist QueryHits with the ER Antagonist Query
Scaffolds
1027 hits
631 π-scaffolds
364 scaffolds
261 ringsystems3D query
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M. Wagener
Results: Matching the QueryResults: Matching the Query
LY-357489
OH
O
O
OH
N
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M. Wagener
SRR
R
O R
RR
R
R
R
R
R
RR
R
R
O
R
R
SR
R
O
R
S
O
R
R
RN
R
R
R
R
OH
OHO
N
RU-39411
Other Scaffolds ...Other Scaffolds ...
SOHOH
O
N
LY-335124 O OH
OH
ON
EM-652OH
OH
ON
LY-326315
N
OH
O
OH
N
pipendoxifene
S
O
OH
O
O
N
arzoxifene
SOH
OH
O
ON
raloxifene
OH
O
O
OH
N
LY-357489
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M. Wagener
ConclusionsConclusions
3D Database Searchingas valuable tool for virtual screening
2D-to-3D Conversion
based on an automated assembly of fragments
Conformational Analysisto take into account molecular flexibility
Pharmacophorescomprise features essential for biological activity
Scaffold Hoppingfocuses on similar spatial orientation of substituents
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M. Wagener
Further ReadingFurther Reading
• A.C. Good, J.S. Mason Three-Dimensional Structure Database Searches. in: Reviews in Computational Chemistry, K.B. Lipkowitz, D.B. Boyd, Ed., VCH Publishers, 1996, 67-117.
• D.T. Manallack Getting that Hit: 3D Database Searching in Drug Discovery. Drug Disc. Today 1996, 1, 231-238.
• M.A. Miller Chemical Database Techniques in Drug Discovery. Nat. Rev. Drug Disc. 2002, 1, 220-227.
• H.J. Böhm, G. Klebe, H. Kubinyi Wirkstoffdesign. Spektrum Verlag, 1996.
available only in German, but really worth the effort.