1 Miklós Vargyas May, 2005 Compound Library Annotation

Slide 2 Compound Library Annotation UGM Compound Library Annotation Overview of the Screen Package Virtual screening Optimized dissimilarity metrics Clustering Library Annotation – a real-life application of the Screen tool Approach #1: use command line applications Approach #2: API programming

Slide 3 Compound Library Annotation UGM Overview of the Screen Package queries targets hypothesis fingerprint metric target fingerprints Virtual hits

Slide 4 Compound Library Annotation UGM Need for Optimization

Slide 5 Compound Library Annotation UGM Optimized Metrics asymmetry factor scaling factor asymmetry factor weights

Slide 6 Compound Library Annotation UGM Improved Similarity by Optimization

Slide 7 Compound Library Annotation UGM Enrichment by Optimization

Slide 8 Compound Library Annotation UGM Clustering 8 active compound sets ACE inhibitors angiotensin 2 antagonists D2 antagonists delta antagonists FTP antagonists mGluR1 antagonists Thrombin inhibitors 5-HT3-antagonists

Slide 9 Compound Library Annotation UGM Ward Centroids

Slide 10 Compound Library Annotation UGM Maximum Common Substructure Clustering

Slide 11 Compound Library Annotation UGM Compound Library Annotation Act ACE =0.5Act ß2 =0.98 Act ACE =0.78 Act ß2 =0.45 Annotate library: predicted activity in some therapeutic areas

Slide 12 Compound Library Annotation UGM Similarity Based Activity Prediction Act ACE =0.55 Act ß2 =0.98 Use sets of known actives to predict activity of compounds

Slide 13 Compound Library Annotation UGM Approach #1: Off the Shelf ChemAxon Tools Parameter setting Pharmacophore fingerprint Tanimoto dissimilarity metric Median Pharmacophore Hypothesis screenmd library.sdf ace.sdf \ –o SDF annotated-library.sdf \ -k PF –M Tanimoto –H Median

Slide 14 Compound Library Annotation UGM Single Active Family

Slide 15 Compound Library Annotation UGM Multiple Active Families screenmd library.sdf ace.sdf \ -o SDF lib-ace.sdf -k PF –M Tanimoto –H Median screenmd lib-ace.sdf beta2.sdf \ -o SDF lib-ace+beta2.sdf -k PF –M Tanimoto –H Median screenmd lib-ace+beta2.sdf delta.sdf \ -o SDF lib-ace+beta2+delta.sdf -k PF –M Tanimoto \ –H Median screenmd lib-ace+beta2+delta.sdf D2.sdf \ -o SDF lib-ace+beta2+delta+D2.sdf -k PF –M Tanimoto \ –H Median...

Slide 16 Compound Library Annotation UGM Annotated Library File

Slide 17 Compound Library Annotation UGM Approach #2: Using ChemAxon JChem API API programming – custom solution PharmacophoreFingerprint and the MolecularDescriptor class hierarchy Tanimoto dissimilarity calculation Median Hypothesis calculation Description generation for structure in SDfile Writing structures in SDfile

Slide 18 Compound Library Annotation UGM MolecularDescriptor class hierarchy Molecular Descriptor Chemical Fingerprint Pharmacophore Fingerprint MACCS BCUT CUSTOM

Slide 19 Compound Library Annotation UGM MolecularDescriptor Sets Molecular Descriptor Set Molecular Descriptor 1 (e.g. CFp) Molecular Descriptor 2 (e.g. PFp) Molecular Descriptor 3 (e.g. logP)

Slide 20 Compound Library Annotation UGM Dissimilarity Calculation MDSet s1 = MDSet.newInstance( new String[]{CF,PF,LogP} ) MDSet s2 = MDSet.newInstance( new String[]{CF,PF,LogP} )... Generate s1 and s2 somehow... System.out.println( dissimilarity(s1,s2) = + s1.getDissimilarity( s2 ) );

Slide 21 Compound Library Annotation UGM Tanimoto Dissimilarity Calculation MDSet s1 = MDSet.newInstance( new String[]{PF} ) MDSet s2 = MDSet.newInstance( new String[]{PF} )... Generate s1 and s2 somehow... PharmacophoreFingerprint pf1 = s1.getDescriptor(0); PharmacophoreFingerprint pf2 = s2.getDescriptor(0); System.out.println( Tanimoto(pf1,pf2) = + pf1.getTanimoto( pf2 ) );

Slide 22 Compound Library Annotation UGM Median Hypothesis Calculation MDSet s1 = MDSet.newInstance( new String[]{PF} ) MDSet s2 = MDSet.newInstance( new String[]{PF} )... Generate s1 and s2 somehow... MDHypothesisGenerator medianHypoGenerator = MDHypothesisCreator.create( "Median" ); medianHypoGenerator.add( s1 ); medianHypoGenerator.add( s2 ); MDSet hypothesis = medianHypoGenerator.generate();

Slide 23 Compound Library Annotation UGM Reading Descriptors from Structure File MDFileReader inputReader = new MDFileReader( library.sdf, MDSet.newInstance( new String[]{"PF"} ) ); MDSet mdRead = inputReader.next();

Slide 24 Compound Library Annotation UGM Writing structures in SDfile MolExporter outputWriter = new MolExporter( new PrintStream( new BufferedOutputStream( new FileOutputStream( fileName ))), "sdf"); Molecule m = getAMolecule(); outputWriter.write( m );

Slide 25 Compound Library Annotation UGM LibAnnot class Full source code avaialable at

Slide 26 Compound Library Annotation UGM Future plans New MolecularDescriptors (e.g. 3D Pharmacophore) Non-hierarchical MCS clustering, better GUI Library diversity estimation

Slide 27 Compound Library Annotation UGM Summary Screen+JKlustor for optimized virtual screening and hit set profiling Library annotation by screenmd Library annotation by custom program

Slide 28 Compound Library Annotation UGM Acknowledgements and Credits JKlustor developed by Ferenc Csizmadia et al Optimizer developed by Zsuzsa Szabó PMapper developed by Szilárd Dóránt, Nóra Máté Pharmacophore definitions by György Pirok

Slide 29 Compound Library Annotation UGM Máramaros köz 3/a Budapest, 1037 Hungary Thank you for your attention