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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)

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Java solutions for cheminformatics

Java Solutions for Cheminformatics

Conformer generation

June 2006


The modeling team at elte e tv s lor nd university
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
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
Goal of conformer generation

  • Generating valid 3D molecular structures

  • Finding multiple structures for flexible molecules


History of conformer generation in marvin
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
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 mview1
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 mview2
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
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 plugins1
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 plugins2
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 plugins3
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
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.



Command line conformer tools cxcalc conformers leconformers
Command line conformer tools (cxcalc) pluginsconformers & 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
Command line molecular dynamics tools (cxcalc) pluginsmoldyn

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
Conformer tools API plugins

// 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 capabilities comparison
3D structure generation capabilities pluginsComparison

Corina Marvin

15.2 s

Much faster…


3d structure generation capabilities comparison1
3D structure generation capabilities pluginsComparison

Corina Marvin

5.9 s

Much faster…


3d structure generation capabilities comparison2
3D structure generation capabilities pluginsComparison

Corina Marvin

5.1 s

Much faster…


Result statistics nci 250k database august 2000
Result statistics pluginsNCI 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
Under development pluginswhat 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



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