3d database searching
TRANSCRIPT
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3D Database Searching and
Scaffold Hopping
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Database Searching
Selection of compounds for testing
Generation of new ideas
Validation of proposed structuralrequirements for activity
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Lock-and-Key Principle
. . . the intimate contact between themolecules . . . is possible only with similargeometrical configurations. To use a picture, Iwould say that the enzyme and the substratemust fit together like a lock and key.
Emil Fischer, Ber. Dtsch. Chem. Ges.1894, 27, 2985.
Receptor
Ligand
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3D Database Searching
Docking
Using the lock, find keys that fit
Pharmacophore Search
Look for keys with same features
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Outline
Database Building
2D-to-3D Conversion
Multi-Conformational Databases
Pharmacophoric Searches
Scaffold Databases
Scaffold Hopping
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Available Compound Collections
ACD
NCI
Maybridge
ZINC collection a comprehensive collection
of drug like molecules
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2D-to-3D Conversion
OH
NH
NH
SO
OH
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Fragmentation into Cyclic/Acyclic Parts
OH
NH
NH
S
O
OH
NH
S
O
O
N
S
NH
OH
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Ring Templates
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Joining the Fragments
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Conformational Flexibility
conformationalensemble
low-energyconformation
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Conformational Analysis
Systematic Search
high number of conformers:
e.g. 10 rotatable bonds with 120 steps: 310 ~ 60,000
conformers
Sampling Techniques
Molecular Dynamics, Distance Geometry, SimulatedAnnealing
Poling: Promoting Conformational Variation
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Protein-Ligand Interaction
O
OH
H3
N+O
O
hydrogen bonds
salt bridges
hydrophobe
interactions cation- interactions
metal complexes
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Pharmacophore
A pharmacophore is a specific spatial
arrangement of atoms or functional groupsrequired for a drug molecule to exert aparticular biological effect.
OH
OH
NH
OH
adrenaline
2 - 3
4 - 7.2
6 - 8
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Pharmacophore Elements
Hydrogen bond donors:
Hydrogen bond acceptors:
Hydrophobes:
Positive ionizable groups:
Negative ionizable groups:
O
H
N
O
H
N
O
H
O
N+
H
N
H
N N+
H
H
H
H
O
O
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Pharmacophore Searching
2 - 3
4 - 7.2
6 - 8
3DDatabase
14251druglike compounds
843search hits
7 CPU min
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Alignment of 2 Search Hits
OH
NH
NH
S
O
OH
OH
OH
NH
OH
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Scaffold Hopping
Breaking out of old series: no further optimization possible
patent issues
backup
O
N
O
OH
OH
New Scaffold
O
N
O
OH
OH
S
OH
OH
O
O
N
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Conventional Approaches
Similarity Searchuses overall similarity to retrieve structures
Pharmacophore Search
focuses on features important for receptor-
ligand interaction
S
OH
OH
O
O
N
O
O
F
O
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Scaffold Hopping
GoalFind similar scaffolds, not similar compounds
Approach
1) Generate a non-redundant database of scaffolds2) Store position and orientation of substitution sites3) Use orientation of substitution sites on the query to
identify new scaffolds
ExampleEstrogen antagonists
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Generating the Scaffolds Database
ACD
Organon
Drugs
Scaffolds
scaffoldextraction
canonization
conformational
analysis
R
R
O
R
R
R
N
R
R
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Scaffold Extraction
S
R
R
R
S
R
R
O
R
S
R
R
R
S
OH
OH
O
O
N
ringsystem
scaffold
-scaffold
R R
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Searching the Database
3D query
Scaffolds
suggestedscaffolds
N
R
R
R
R
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Conclusions
3D Database Searching
as valuable tool for virtual screening
2D-to-3D Conversion
based on an automated assembly of fragmentsConformational Analysisto take into account molecular flexibility
Pharmacophores
comprise features essential for biological activityScaffold Hopping
focuses on similar spatial orientation of substituents