Chemical Space Navigation using Spot Fire Decision Site

Chemical Space Navigation using Spot. Fire Decision. Site Anne Marie Munk Jørgensen, Morten Langgård & Jacob Flemming Hansen H. Lundbeck A/S

Pogo. Prop System Overview SDfile Calculate descriptors Structures and parameters Do Statistics H. Lundbeck A/S

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…. . H. Lundbeck A/S

Data collection Chem. Index CNS MDDR, Beilstein, Chemfinder, Pharm. Sub H. Lundbeck A/S Corina Qik. Prop CNS database 373 compounds with known CNS activity. Structures and calculated parameters

CNS model 12 descriptors 3 components, R 2 X=0. 71 Blue dots define: : CNS drug space CNS World H. Lundbeck A/S

Spot. Fire as Chemical space navigator • Chem 3 D principal component plot defines the CNS ”world” – and we use Spot. Fire to navigate in this world. • Chem GPS (Oprea & Gottfries, J. Comb. Chem 2001) H. Lundbeck A/S

… Some technical issues…. . H. Lundbeck A/S

PCA calculation • … was done with SIMCA (Umetrics) PCA tool in Spot. Fire: - important parameters like dist 2 Model and Hotelling. T 2 are missing in Spot. Fire - 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 …… H. Lundbeck A/S

Statistics • …. Were done by use of a perl script. ”New column by expression” works fine but only for relatively short function definition…. . (((((( 0. 279851 *( ”COL 3" - 0. 874500 )/0. 597500) - ( 0. 151222 *( ”COL 5" 0. 081360 )/0. 273800)) + ( 0. 289006 *( ”COL 8" - 3. 942000 )/2. 580000)) + ( 0. 424097 *( ”COL 2" - 396. 400000 )/88. 470000)) + ( 0. 050571 *( ”COL 3" - 559. 400000 )/118. 300000)) + ( 0. 290386 *( ”COL 4" - 236. 100000 )/117. 800000)) - ( 0. 156653 *( ”COL 8" - 90. 130000 )/57. 770000)) + ( 0. 782491 *( ”COL 11" - 193. 500000 )/103. 400000)) + ( 0. 109637 *( ”COL 12" - 31. 640000 )/45. 550000)) + ( 0. 454716 *( ”COL 15" - 944. 500000 )/289. 300000)) - ( 0. 176048 *( ”COL 16" - 1. 066000 )/1. 071000)) + ( 0. 214576 *( ”COL 19" - 4. 940000 )/2. 264000)) H. Lundbeck A/S

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 email when the job has finished. H. Lundbeck A/S

Spot. Fire 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 H. Lundbeck A/S

Use of the setup…. and the CNS model… H. Lundbeck A/S

Input Structures … can come from several sources • Compounds we are considering for purchase • Compounds which we plan to synthesize H. Lundbeck A/S

Structure Property Calculations Structures from ISIS Corina 2 D->3 D Qikprop PSA desc. + Tabulated output CN(C)CCCC 1(OCc 2 cc(C#N)ccc 12)c 3[c]cc(F)cc 3 Descriptors: PSA’s: SASA, FOSA, WPSA, …… Counts: MW, #HBD, #HBA, #ROT, #…. . Models for: log. P, log. S, CNS, Caco 2, …… H. Lundbeck A/S Merge with CNS DB of launched drugs (Chem GPS)

Principal Component Analysis (PCA) How could this loading plot be included in Spotfire? H. Lundbeck A/S

Distance to model H. Lundbeck A/S

Non CNS compounds from WDI H. Lundbeck A/S

Distance to model, example Why is Hot. T 2 large? User defined ”details on demand” facility…. . H. Lundbeck A/S

Spot. Fire Guides • Lipinski filtering on defined columns • Make histograms of selected descriptors H. Lundbeck A/S

Clustering of structures Diversity selection structural clustering works fine in Spot. Fire Get one structure from each cluster -preferably the one in the center of each cluster not possible in Spot. Fire H. Lundbeck A/S

Suggestion to development in Spot. Fire • 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 H. Lundbeck A/S