Kein Folientitel

1
3D Database Searching and Pharmacophore Models
2
Drug Design Techniques
TARGET structure

• "Small molecule" Modelling
• Superimposition of known ligands
• Conformational analysis
• Pharmacophore hypotheses
• 3D-Database searches

• Structure-based Design
• Search for "hot spots"
• Pharmacophore hypotheses
• 3D-Database searches
• Docking
• De-novo Design

3
3D-Database Searching

• 3D models of small molecules can be stored in
  databases
• 3D structures may be derived from experimental
  data (e.g. Cambridge Crystallographic database)
  or built by 2D?3D conversion programs (e.g.
  Concord or Corina)
• Search queries can be formulated at any level of
  "fuzzyness"
• detailed, like "aromatic Carbon in 5.1Å distance
  from primary amine"
• fuzzy, like "any Hbond acceptor in 5 to 9Å
  distance from any heavy atom"
• Conformational flexibility is tackled either by
  precalculation/storage of multiple conformers or
  by restricted conformational search "on-the-fly"

4
Case study HIV protease inhibitors
5
Small-molecule superimposition

• Goal Alignment of corresponding pharmacophoric
  groups in order to derive a 3D pharmacophore
  model
• Superimposition can be performed manually or
  automatically
• Automatic superimposition techniques should
  consider pharmacophoric properties (e.g. H-bond
  donors/acceptors, charges, shape etc.)
• Conformational flexibility should be considered
• Two standard programs SEAL (Kearsley et al.,
  MSD) and FLEXS (Lemmen et al., GMD)

6
Small-molecule superimposition
Isn't it just obvious how to superimpose these
two molecules?
7
Small-molecule superimposition
8
Small-molecule superimposition
...but is it the truth?
This looks much more reasonable...
9
Small-molecule superimposition
The molecular electrostatic potential (MEP) gives
an additional hint for the proposed
superimposition
10
Small-molecule superimposition
11
Small-molecule superimposition
OK, our manual superimposition was correct...
...but can we calculate this automatically???
12
Small-molecule superimposition

• FlexS is able to calculate the (almost) correct
  superpositioning mode in just a few seconds
• FlexS considers H-bonding pattern and shape
  complementarity for superpositioning

13
Small-molecule superimposition Implications for
Drug Design
Designed molecule (red) has higher affinity than
flexible molecules (green)