1. Java Solutions for Cheminformatics June 2006 Conformer generation

2. May 2006 The modeling team at ELTE (Eötvös Loránd University) Ödön Farkas –General leadership –Geometry optimization –Fragment fuse –Search involving geometry constraints, etc. Imre Jákli –Molecular dynamics (MD) –Database connection Adrián Kalászi –Molecular mechanics –Drug design tools (3D pharmacophore model) –Conformer search via MD Gábor Imre –3D builder scheduling –Fragment-atom fuse (v2) –Minkowski-based build –Debug tools Students: Krisztina Szölgyén, László Antall

3. May 2006 Conformers are locally stable structures of a molecule. –Conformers are often called rotamers, however rings may also have different conformers which are not rotamers. Intermediate structures, corresponding to molecular motion, are conformations and should not be considered as conformers. The lowest energy conformer can only be found certainly if all conformers are known. The distribution of conformers can be approximated using the calculated conformational energy. Conformer generation / basic concepts

4. May 2006 Goal of conformer generation Generating valid 3D molecular structures Finding multiple structures for flexible molecules

5. May 2006 First approach based on a generalized Minkowski metric G. Imre, G. Veress, A. Volford, Ö. Farkas Molecules from the Minkowski space: an approach to building 3D molecular structures J. Mol. Struct. (Theochem) 666-667, 51 (2003) Due to problems with chirality and slow computational time we introduced an atom-by-atom fuse method G. Imre, Ö. Farkas 3D Structure Prediction and Conformational Analysis 7th ICCS, June 5 - 9, 2005 Noordwijkerhout, The Netherlands Scheduling is important Faster and reliable process Frequent use of geometry optimization may slow down the process Current version is based on fusing fragments History of conformer generation in Marvin

6. May 2006 Key algorithms used or developed for conformer generation Quaternion fit (JQuatFit) Based on the work of Hamilton http://en.wikipedia.org/wiki/Quaternion Can fit two molecular structures via non-iterative, linear scaling, extremely fast method. Used for fitting common atoms for fusing fragments Substructure3DSearch Based on the substructure search implemented by ChemAxon Simplified for fast exact match (using graph invariant) Extended with geometry matching (using quatfit) to separate conformers high/low priority matching for selecting suitable fuse positions geometry constrained topological matching for fragment re-use Can quickly distinguish conformers with optional diversity limit

7. May 2006 Conformer tools in the GUI MSketch/MView Draw a molecule

8. May 2006 Conformer tools in the GUI MSketch/MView Draw a molecule Adjust Clean/3D mode Fast build: old algorithm, no Hydrogens Fine build: new algorithm, automatically adds Hydrogens Build or optimize: build only for non 3D structures Optimize: just optimize Press Ctrl-3 to process

9. May 2006 Conformer tools in the GUI MSketch/MView Pressing F7 changes for 3D rotation mode to change the viewpoint Previously Ctrl-F generated conformers, now it only displays if they are available The new Conformer plugin is advised for conformer generation

10. May 2006 Conformer tools in the GUI MSketch/MView calculator plugins The conformer plugin allows easy access to the most important options: Output as molecule array or storage in single molecule Variable optimization criteria Multiple or single conformer Maximum conformer count Time limit for the process Hyperfine mode for thorough checking of conformers H-bond visualization Access to old algorithm

11. May 2006 Conformer tools in the GUI MSketch/MView calculator plugins The conformer plugin allows easy access to the most important options: Output as molecule array or storage in single molecule Variable optimization criteria Multiple or single conformer Maximum conformer count Time limit for the process Hyperfine mode for thorough checking of conformers H-bond visualization Access to old algorithm

12. May 2006 Conformer tools in the GUI MSketch/MView calculator plugins The conformers can also be stored as a property of the molecule (available in mrv, sdf) Single molecule appears as a result and Ctrl-F displays the stored the individual conformers The desired conformer to display can be selected The selected conformer should be confirmed.

13. May 2006 Conformer tools in the GUI MSketch/MView calculator plugins The stored conformers then will appear when Ctrl-F is pressed.

14. May 2006 Molecular dynamics in the GUI MSketch/MView calculator plugins The stored conformers then will appear when Ctrl-F is pressed. The flexibility of the molecule can be studied via molecular dynamics.

15. May 2006 Molecular dynamics in the GUI MSketch/MView calculator plugins

16. May 2006 Command line conformer tools (cxcalc) conformers & leconformers Usage: cxcalc [general options] [input files/strings] conformers [conformers options] [input files/strings] conformers options: -h, --help this help message -f, --format should be a 3D format (default: sdf) -m, --maxconformers (default: 100) -s, --saveconfdesc [true|false] if true a single conformer is saved with a property containing conformer information (default: false) -e, --hyperfine [true|false] if true hyperfine option is set (default: false) -o, --oldalg [true|false] if true old (before Marvin 4.1) algorithm is used for calculation (default: false) -y, --prehydrogenize [true|false] if true prehydrogenize is done before calculation, if false calculation is done without hydrogens (available only with old algorithm, default: false) -l, --timelimit (default: 900) -O, --optimization [0|1|2|3] conformer generation optimiztaion limit (default: 1) # cxcalc conformers -m 250 -s true test.sdf

17. May 2006 Command line molecular dynamics tools (cxcalc) moldyn Usage: cxcalc [general options] [input files/strings] moldyn [moldyn options] [input files/strings] moldyn options: -h, --help this help message -x, --forcefield [dreiding] forcefield used for calculation (default: dreiding) -i, --integrator [positionverlet|velocityverlet|leapfrog] integrator type used for calculation (default: velocityverlet) -n, --stepno (default: 1000) -m, --steptime (default: 0.1) -T, --temperature (default: 300 K) -j, --trajectorytype [mol|sdf] type of output mol: series of mol frames sdf: series of sdf frames (default: sdf) Example: cxcalc moldyn test.mol

18. May 2006 Conformer tools API // read input molecule MolImporter mi = new MolImporter("test.mol"); Molecule mol = mi.read(); mi.close(); // create plugin ConformerPlugin plugin = new ConformerPlugin(); // set target molecule plugin.setInputMolecule(mol); // set parameters for calculation plugin.setMaxNumberOfConformers(400); plugin.setTimelimit(900); // run the calculation plugin.run(); // get results Molecule[] conformers = plugin.getConformers(); int conformerCount = plugin.getConformerCount(); Molecule m; for (int i = 0; i < conformerCount; ++i) { m = conformers[i]; // same as m = plugin.getConformer(i); // do something with the conformer... } // do something with the results...

19. May 2006 3D structure generation capabilities Comparison CorinaMarvin 15.2 s Much faster…

20. May 2006 3D structure generation capabilities Comparison CorinaMarvin 5.9 s Much faster…

21. May 2006 3D structure generation capabilities Comparison CorinaMarvin 5.1 s Much faster…

22. May 2006 Result statistics NCI 250K database (August, 2000) 1 st round Current method with 120 sec. time limit Conversion rate: 99.92% (failed 193 of 250251) Avarage time is 0.65 sec/molecule 2 nd round Old method on the 193 previously failing structures Overall conversion rate: 99.994% (failed 13)

23. May 2006 Under development what to expect in the near future 100% conversion rate for valid, medium size structures Optional conformer diversity limit Server version Carrying built up fragments for consequent processes Store and use fragment database Further speedup MMFF94 force field

24. May 2006 Acknowledgements