M. Wagener 3D Database Searching and Scaffold Hopping Markus Wagener NV Organon.
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Transcript of M. Wagener 3D Database Searching and Scaffold Hopping Markus Wagener NV Organon.
M. Wagener
3D Database Searching and 3D Database Searching and Scaffold HoppingScaffold Hopping
Markus Wagener
NV Organon
M. Wagener
Database SearchingDatabase Searching
• Selection of compounds for testing
• Generation of new ideas
• Validation of proposed structural requirements for activity
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
M. Wagener
3D Database Searching3D Database Searching
Docking
Using the lock, find keys that fit
Pharmacophore Search
Look for keys with same features
M. Wagener
OutlineOutline
• Database Building– 2D-to-3D Conversion– Multi-Conformational Databases
• Pharmacophoric Searches
• Scaffold Databases
• Scaffold Hopping
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/
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.
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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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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Conformational FlexibilityConformational Flexibility
conformationalensemble
low-energyconformation
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
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
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
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
M. Wagener
Protein-Ligand InteractionProtein-Ligand Interaction
O
OH
H3N+O
O
• hydrogen bonds• salt bridges• hydrophobe
interactions• cation-π interactions• metal complexes
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.
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
M. Wagener
Pharmacophore SearchingPharmacophore Searching
2 - 3 Å
4 - 7.2 Å
6 - 8 Å
3DDatabase
14251druglike compounds
843search hits
7 CPU min
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:
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
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
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
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
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
M. Wagener
Searching the DatabaseSearching the Database
3D query
Scaffolds
suggestedscaffolds
N
R
R
R
R
M. Wagener
raloxifene
substitution sites
+ aromatic ring
+ ring orientation
+ directions
3D query
+ shape
A Query for ER antagonistsA Query for ER antagonists
M. Wagener
Hits with the ER Antagonist QueryHits with the ER Antagonist Query
Scaffolds
1027 hits
631 π-scaffolds
364 scaffolds
261 ringsystems3D query
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
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
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.