1. Chemical Space Navigation using SpotFire DecisionSite
Anne Marie Munk Jørgensen,
Morten Langgård
& Jacob Flemming Hansen
Anne Marie Munk Jørgensen,
Morten Langgård
& Jacob Flemming Hansen
H. Lundbeck A/S

2. PogoProp System Overview
SDfile
Calculate
descriptors
Structures
and
parameters Do
Statistics

3. Compound library profiling
10 years ago: Diversity
1997: Lipinski’s rule of 5 + diversity
Now: very high focus on how biologically relevant the screening collection is.
Computational methods to predict drug likeness, CNS likeness….
High throughput is not enough … to get high output…..

4. Data collection ChemIndex CNS database CNS Corina QikProp
373 compounds with known CNS activity.
Structures and calculated parameters
parameters
MDDR,
Beilstein,
Chemfinder,
PharmSub

5. CNS model
12 descriptors 
3 components,
R2X=0.71
Blue dots define::
CNS drug space
CNS World

6. SpotFire as Chemical space navigator
Chem 3D principal component plot defines the CNS ”world” – and we use SpotFire to navigate in this world.
Chem GPS (Oprea & Gottfries,
J. Comb. Chem 2001)

7. … Some technical issues…..

8. PCA calculation … was done with SIMCA (Umetrics) PCA tool in SpotFire:
- important parameters like dist2Model and HotellingT2 are missing in SpotFire
- It is not possible to save the model and use
it for later predictions (perhaps in a template )
- Loading plot is missing
Formulas extracted from Simca and used automatically on new data ……

9. …. Were done by use of a perl script.
Statistics
…. Were done by use of a perl script.
”New column by expression” works fine but only for relatively short function definition…..
(((((((((((( *( ”COL3" )/ ) - ( *( ”COL5" )/ )) + ( *( ”COL8" )/ )) + ( *( ”COL2" )/ )) + ( *( ”COL3" )/ )) + ( *( ”COL4" )/ )) - ( *( ”COL8" )/ )) + ( *( ”COL11" )/ )) + ( *( ”COL12" )/ )) + ( *( ”COL15" )/ )) - ( *( ”COL16" )/ )) + ( *( ”COL19" )/ ))

10. User Interface Intranet based
You select User name, Job name, browse to the sdfile and write the name of the field containing the structure identifier  Go
Get an when the job has finished.

11. SpotFire call back function
With this function, it is possible to make
a selection of the compounds one wants to
synthesize or buy, and communicate this back
to the database for further use  easy to make
a list of compounds one can send to the external
provider or the technicians.
This function was created by our IT team. They created it in almost the same way as the text book example

12. Use of the setup…. and the CNS model…

13. Input Structures
… can come from several sources
Compounds we are considering for purchase
Compounds which we plan to synthesize

14. Structure Property Calculations
Corina
2D->3D
CN(C)CCCC1(OCc2cc(C#N)ccc12)c3[c]cc(F)cc3
Structures from ISIS
Qikprop
PSA desc. +
Descriptors:
PSA’s: SASA,FOSA,WPSA,……
Counts: MW,#HBD,#HBA,#ROT,#…..
Models for:
logP, logS, CNS, Caco2, ……
Tabulated output
Merge with CNS DB of launched drugs (Chem GPS)

15. Principal Component Analysis (PCA)
How could this loading plot be included in Spotfire?

16. Distance to model

17. Non CNS compounds from WDI

18. Distance to model, example
Why is HotT2 large? User defined ”details on demand” facility…..

19. SpotFire Guides
Lipinski filtering on defined columns
Make histograms of selected descriptors

20. Clustering of structures
Diversity selection  structural clustering
works fine in SpotFire
Get one structure
from each cluster
preferably the
one in the center
of each cluster
not possible in SpotFire

21. Suggestion to development in SpotFire
More advanced statistic tools wanted
- it should be possible to save a model as a template and use it for prediction
- Loading plot should be included
- 99/95% ellipse should be shown
Easier way of handling expressions
In clustering analysis, it should be possible to get the center structure from each cluster
User defined “details on demand” function