3D Database Searching and Scaffold Hopping

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3D Database Searching and Scaffold Hopping

• Markus Wagener
• NV Organon

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Database Searching

• Selection of compounds for testing
• Generation of new ideas
• Validation of proposed structural requirements
  for activity

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Lock-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.

Ligand
Receptor
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3D Database Searching
DockingUsing the lock, find keys that
fit Pharmacophore SearchLook 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
Size x 1000
http//cactus.nci.nih.gov/ncidb2/
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2D-to-3D Conversion Corina
J. Sadowski, J. Gasteiger Chem. Rev. 1993, 93,
2567.
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Fragmentation into Cyclic/Acyclic Parts
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Ring Templates
27 kJ/Mol
18 kJ/Mol
50 kJ/Mol
25 kJ/Mol
56 kJ/Mol
43 kJ/Mol
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Joining of Ring Templates Cubane
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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 conformerse.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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Conformational Flexibility
Energy kJ/Mol
Torsion Angle
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Conformational Poling
Epole
A. Smellie, S.L. Teig, P. Towbin J. Comp. Chem.
1995, 16, 171.
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Lock-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

Ligand
Receptor
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Protein-Ligand Interaction

• hydrogen bonds
• salt bridges
• hydrophobe interactions
• cation-p interactions
• metal complexes

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Pharmacophore Definition

• A pharmacophore is a specific spatial arrangement
  of atoms or functional groups required for a drug
  molecule to exert a particular biological effect.

adrenaline
adapted from C.D. Strader et al. J. Biol. Chem.
1989, 264, 13572.
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Pharmacophore Elements
Hydrogen bond donors
Hydrogen bond acceptors
Hydrophobes
Positive ionizable groups
Negative ionizable groups
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Pharmacophore Searching
7 CPU min
14251druglike compounds
843search hits
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Alignment of 2 Search Hits
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Quality of the Pharmacophore

• Adrenergic agonists

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Scaffold Hopping

• Breaking out of old series
• no further optimization possible
• patent issues
• backup

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Conventional Approaches

• Similarity Searchuses overall similarity to
  retrieve structures
• Pharmacophore Searchfocuses on features
  important for receptor-ligand interaction

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Scaffold Hopping

• GoalFind similar scaffolds, not similar
  compounds
• Approach1) 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
scaffoldextraction canonization
conformational analysis
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Scaffold Extraction
ringsystem
scaffold
p-scaffold
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Searching the Database
suggestedscaffolds
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A Query for ER antagonists
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Hits with the ER Antagonist Query
1027 hits 631 p-scaffolds 364 scaffolds 261 ri
ngsystems
3D query
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Results Matching the Query
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Other Scaffolds ...
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Conclusions

• 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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Further 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.