Java Solutions for Cheminformatics

Java Solutions for Cheminformatics Conformer generation June 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

Conformer generation / basic concepts • 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.

Goal of conformer generation • Generating valid 3D molecular structures • Finding multiple structures for flexible molecules

History of conformer generation in Marvin • First approach based on a generalized Minkowski metricG. 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 methodG. 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

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

Conformer tools in the GUI MSketch/MView Draw a molecule

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

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 Conformerplugin is advised for conformer generation

Conformer tools in the GUI MSketch/MView calculator plugins • The conformer plugin allows easy access tothe most importantoptions: • 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

Conformer tools in the GUI MSketch/MView calculator plugins The conformers canalso be stored as aproperty of the molecule(available in mrv, sdf) • Single molecule appearsas a result and “Ctrl-F”displays the stored the individual conformers • The desired conformer to display can be selected • The selected conformershould be confirmed.

Conformer tools in the GUI MSketch/MView calculator plugins The stored conformersthen will appear when “Ctrl-F” is pressed.

Molecular dynamics in the GUI MSketch/MView calculator plugins The stored conformersthen will appear when “Ctrl-F” is pressed. The flexibility of the molecule can be studiedvia molecular dynamics.

Molecular dynamics in the GUI MSketch/MView calculator plugins

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 <output format> should be a 3D format (default: sdf) -m, --maxconformers <maximum number of conformers to be generated> (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 <timelimit for calculation in sec> (default: 900) -O, --optimization [0|1|2|3] conformer generation optimiztaion limit (default: 1) # cxcalc conformers -m 250 -s true test.sdf

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 <number of simulation steps> (default: 1000) -m, --steptime <time between steps in femtoseconds> (default: 0.1) -T, --temperature <temperature in Kelvin> (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

Conformer tools API // read input molecule MolImporter mi = newMolImporter("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 ...

3D structure generation capabilitiesComparison Corina Marvin 15.2 s Much faster…

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

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

Acknowledgements

Java Solutions for Cheminformatics