CCDC_Intro proposal for Industry day

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Insight into Molecular Geometry and Interactions
using Small Molecule Crystallographic Data
John Liebeschuetz Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge,
UK john_at_ccdc.cam.ac.uk
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How much Data is Available?
Growth of the Cambridge Structural Database over
40 years

• CSD Growth
• 1970-2006

Predicted Growth to 2010
gt500,000 entries during 2009

• 419,768 entries June 2007

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CSD Data Content

• Literature Reference
• G. Bringmann, M.
  Ochse,
• K. Wolf, J. Kraus, K. Peters,
• E-M. Peters, M. Herderich,
• L. Ake, F. Tayman
• Phytochemistry 51,1999,
  271
• Other text
• R-factor .0506
• Colour pale yellow
• Habit acicular
• Polymorph Form IV
• Source Rothmannia longiflora
• 4-Oxonicotinamide-1-(1-beta-D-2,3,5-tri-O-acet
  yl-
• ribofuranoside)
• C17 H20 N2 O9

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Molecular Interactions as well as Geometry
HEPPEX
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Cambridge Structural Database System
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Using Structural Data in molecular modelling for
pharmaceutical design

• Intramolecular 3D geometry
• Designing in the desired Conformer
• Validation that models have correct geometry
• Intermolecular Interactions between molecules
• Design of pharmacophores
• Validation of interactions found during
  modelling
• Identification of new ways to satisfy binding
  motifs
• Knowledge-based scoring functions for docking

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Designing in the right Conformation (1)

• It is possible using Conquest to generate
  incidence histograms for any geometric feature ,
  for any substructure, if sufficient high quality
  structures including that substructure, are
  present in the CSD

Brameld. K.A., Kuhn, B., Reuter, D.C. and Stahl,
M. J. Chem. Inf. Mod, 48(1), 1-24 2008)
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Designing in the right Conformation (2)

• Sulphonamide is common in drug molecules. Its
  conformational behaviour well captured by CSD
• Ortho Substitution (Blue histogram) shifts the
  maximum
• Pyramidalisation of the N of the sulphonamide
  can also be explored. This is a common effect in
  sulphonamides (and piperidines) but is poorly
  reproduced by modelling software

Brameld. K.A., Kuhn, B., Reuter, D.C. and Stahl,
M. J. Chem. Inf. Mod, 48(1), 1-24 2008)
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Designing in the right Conformation (3) Example
1
CSD analysis indicates the bioactive conformation
is stable only for most active structure
Brameld. K.A., Kuhn, B., Reuter, D.C. and Stahl,
M. J. Chem. Inf. Mod, 48(1), 1-24 2008)
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Validation of Model Geometry Mogul

• Rapid access of geometric information from the
  CSD
• Incorporates pre-computed libraries of bond
  lengths, valence angles and torsion angles
• gt20 million individual geometrical parameters
  derived entirely from the CSD and updated
  annually
• Sketch or import molecule, then click on feature
  of interest to view distribution, mean values and
  statistics

Bruno et al., J. Chem. Inf. Comput. Sci., 44,
2133-2144, 2004
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Validation of PDB Ligand Geometry

• PDB structures suffer from less well defined
  electron density
• Protein X-Ray refinement force fields often are
  poorly parameterised to reproduce ligand
  geometries
• Sometimes protein crystallographers start with a
  poor ligand model

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Validation of Ligand structures in the PDB via
Protein/Ligand analysis tool Relibase
www.ccdc.cam.ac.uk
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Validation of ligand structures found in the PDB
Ligand from 1HAK, Two abnormal torsions indicated
Further examination reveals the piperidine to be
Boat form
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Validation of ligand structures found in the PDB
using Mogul

• 15 of 100 recent PDB entries have ligand
  geometry that are almost certainly in
  significant error (in house analysis using
  Relibase/Mogul)
• The good news - For structures deposited before
  2000 the figure is 26

2006
Pre 2000
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Designing in the right Conformation (3) Large
Rings
Brameld. K.A., Kuhn, B., Reuter, D.C. and Stahl,
M. J. Chem. Inf. Mod, 48(1), 1-24 2008)
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Validation of ligand structures found in the PDB
Ligand from 1HAK, Two abnormal torsions indicated
Further examination reveals the piperidine to be
Boat form
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Mogul 1.3 Ring Conformations

• Mogul currently holds data on bonds, angles and
  torsions.
• In the 2010 release of the Cambridge Structural
  Database System Mogul will also contain a
  comprehensive ring knowledge base
• Ring libraries from a-Mogul 1.3 have been
  introduced into Gold 4.1 to allow knowledge-
  based ring-flexing during docking

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A Knowledge Base of Intermolecular Interactions
IsoStar

• Experimental data from
• Cambridge Structural Database
• Protein Data Bank (protein-ligand complexes only)
• Theoretical potential energy minima (DMA, IMPT)
• Typical Uses
• Probability of an interaction occurring
• Preferred geometries
• Design Strategies

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IsoStar Methodology
central group -CONH2
contact group NH

• Search CSD or PDB for structures containing
  contact
• Superimpose hits and display distribution

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IsoStar Scatterplots vs. Density MapsN-H donors
around amide CO
Scatterplot
Contour surface
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IsoStar indole and isoxazole interactions with
faces of phenyl rings
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Using Intermolecular information to build
pharmacophores from proteins

• Use intermolecular information (IsoStar) to map
  a protein binding site (e.g. using SuperStar, an
  extra module to the CSDS )
• Create a pharmacophore from this information
  (possible in SuperStar)

c.f. GRID/FLAP
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Motif searching

• Certain signature interaction motifs might be
  key to identifying inhibitor substructures of
  interest. Can we identify such motifs in the CSD
  and thereby uncover new ideas?
• Materials Mercury A new tool for the drug
  development and crystal design community
• Most tools are specific to small molecule
  crystals ....
• However .

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Packing Feature Search

• Comparison of crystal structures polymorphs,
  solvates etc can identify significant packing
  features.
• We can then search the CSD using Packing Feature
  Search

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H-bonding Motif Search Kinase Binding Motifs
Set up a Packing Feature Search around Hinge
Region
CDK2 Complex 1ke8
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H-bonding Motif Search Kinase Binding Motifs
MISTOX
WUSQAC
Provides ideas for new motifs Fragment based
design
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Knowledge-based scoring using small molecule
structural data

• Protein/Ligand Docking relies on a scoring
  function to rank binding poses
• Scoring functions may be Molecular Mechanics
  based, Empirical or Knowledge Based
• A Knowledge Based score is calculated by the sum
  of atom-atom potentials derived from a
  crystallographic database
• The atom-atom potential - log
• Knowledge based scoring functions (PMF, Bleep,
  DrugScore, ASP) have been developed using
  protein-ligand data (PDB)
• The CSD contains better resolved structures and a
  much greater variety of chemical functionality
  than the PDB
• DrugScoreCSD has demonstrably improved
  performance over DrugScore (Velec, Gohlke
  Klebe, J. Med. Chem., 48 (2005), 6296 )

observed interactions
reference state
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Uses of Small Molecule Structural Data in Drug
Design Conclusions

• Use in Model Validation -
• Geometry of designed synthetic candidates
• Geometry of X-ray derived Ligand Structures
• Intermolecular interactions of a candidate
  structure with a model of binding site
• Design of Pharmacophores
• Search for fragments fitting a binding motif
• Creation of robust and versatile Knowledge-Based
  scoring functions for docking

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Acknowledgements
Jana Henneman James Chisholm
Thank you for your attention