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Updated to allow user specified molecule hash generator and included …
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…the orbital information in default molecular hash generator Removed reset method, no need for it Ensured that we output SMILES rather than fragment hashes Updated check for zero atom linkers to avoid redoing cycle detection. 5x speedup for large symmetric/branched structures Keep molecule hash as Long rather than String

Signed-off-by: Rajarshi Guha <rajarshi.guha@gmail.com>
Signed-off-by: John May <john.wilkinsonmay@gmail.com>
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@rajarshi @johnmay
rajarshi authored and johnmay committed Jun 26, 2013
1 parent 091a7b2 commit 376177a
Showing 1 changed file with 61 additions and 33 deletions.
94 changes: 61 additions & 33 deletions src/main/org/openscience/cdk/fragment/MurckoFragmenter.java
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Original file line number Diff line number Diff line change
Expand Up @@ -28,16 +28,23 @@
import org.openscience.cdk.exception.CDKException;
import org.openscience.cdk.graph.ConnectivityChecker;
import org.openscience.cdk.graph.PathTools;
import org.openscience.cdk.graph.SpanningTree;
import org.openscience.cdk.hash.HashGeneratorMaker;
import org.openscience.cdk.hash.MoleculeHashGenerator;
import org.openscience.cdk.interfaces.IAtom;
import org.openscience.cdk.interfaces.IAtomContainer;
import org.openscience.cdk.interfaces.IAtomContainerSet;
import org.openscience.cdk.interfaces.IBond;
import org.openscience.cdk.ringsearch.AllRingsFinder;
import org.openscience.cdk.smiles.SmilesGenerator;

import java.util.ArrayList;
import java.util.Collection;
import java.util.HashMap;
import java.util.HashSet;
import java.util.List;
import java.util.Map;
import java.util.Set;

import java.util.*;

/**
* An implementation of the Murcko fragmenation method {@cdk.cite MURCKO96}.
Expand All @@ -55,7 +62,7 @@
* the largest framework.
*
* @author Rajarshi Guha
* @cdk.module fragment
* @cdk.module fragment
* @cdk.githash
* @cdk.keyword fragment
* @cdk.keyword framework
Expand All @@ -67,18 +74,17 @@ public class MurckoFragmenter implements IFragmenter {
// need to keep track of fragments across recursive calls. Relevant
// for very large symmetric molecules such as
// http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=16129878
private static Set<String> fragmentSet = new HashSet<String>();
private static Set<Long> fragmentSet = new HashSet<Long>();

private static final String IS_SIDECHAIN_ATOM = "sidechain";
private static final String IS_LINKER_ATOM = "linker";
private static final String IS_CONNECTED_TO_RING = "rcon";

MoleculeHashGenerator generator;
SmilesGenerator smigen;

Map<String, IAtomContainer> frameMap = new HashMap<String, IAtomContainer>();
Map<String, IAtomContainer> ringMap = new HashMap<String, IAtomContainer>();

SpanningTree spanningTree;
Map<Long, IAtomContainer> frameMap = new HashMap<Long, IAtomContainer>();
Map<Long, IAtomContainer> ringMap = new HashMap<Long, IAtomContainer>();

boolean singleFrameworkOnly = false;
int minimumFragmentSize = 5;
Expand All @@ -91,7 +97,7 @@ public class MurckoFragmenter implements IFragmenter {
*/
@TestMethod("testMF1,testMF2,testMF3")
public MurckoFragmenter() {
this(false, 5);
this(false, 5, null);
}

/**
Expand All @@ -100,16 +106,34 @@ public MurckoFragmenter() {
* @param singleFrameworkOnly if <code>true</code>, only the true Murcko framework is generated.
* @param minimumFragmentSize the smallest size of fragment to consider
*/
@TestMethod("testSingleFramework")
@TestMethod("testMF1,testMF2,testMF3")
public MurckoFragmenter(boolean singleFrameworkOnly, int minimumFragmentSize) {
this(singleFrameworkOnly, minimumFragmentSize, null);
}

/**
* Instantiate Murcko fragmenter.
*
* @param singleFrameworkOnly if <code>true</code>, only the true Murcko framework is generated.
* @param minimumFragmentSize the smallest size of fragment to consider
* @param generator An instance of a {@link MoleculeHashGenerator} to be used to check for
* duplicate fragments
*/
@TestMethod("testSingleFramework")
public MurckoFragmenter(boolean singleFrameworkOnly, int minimumFragmentSize, MoleculeHashGenerator generator) {
this.singleFrameworkOnly = singleFrameworkOnly;
this.minimumFragmentSize = minimumFragmentSize;

generator = new HashGeneratorMaker().depth(8)
.elemental()
.isotopic()
.charged()
.molecular();
if (generator == null)
this.generator = new HashGeneratorMaker().depth(8)
.elemental()
.isotopic()
.charged()
.orbital()
.molecular();
else this.generator = generator;

smigen = new SmilesGenerator(true);
}

/**
Expand All @@ -120,17 +144,14 @@ public MurckoFragmenter(boolean singleFrameworkOnly, int minimumFragmentSize) {
*/
@TestMethod("testMF1, testMF2, testMF3, testMF4, testMF5, testMF6")
public void generateFragments(IAtomContainer atomContainer) throws CDKException {
fragmentSet = new HashSet<Long>();
frameMap.clear();
ringMap.clear();
run(atomContainer);
}

public void reset() {
fragmentSet = new HashSet<String>();
}

private void run(IAtomContainer atomContainer) throws CDKException {
String hash;
Long hash;

// identify rings
AllRingsFinder arf = new AllRingsFinder(false);
Expand Down Expand Up @@ -158,7 +179,7 @@ private void run(IAtomContainer atomContainer) throws CDKException {
// only add this in if there is actually a framework
// in some cases we might just have rings and sidechains
if (hasframework(currentFramework)) {
hash = Long.toHexString(generator.generate(currentFramework));
hash = generator.generate(currentFramework);

// if we only want the single framework according to Murcko, then
// it was the first framework that is added, since subsequent recursive
Expand All @@ -182,15 +203,15 @@ private void run(IAtomContainer atomContainer) throws CDKException {

List<IBond> bondsToDelete = new ArrayList<IBond>();
for (IBond bond : clone.bonds()) {
if (isZeroAtomLinker(bond, clone)) bondsToDelete.add(bond);
if (isZeroAtomLinker(bond)) bondsToDelete.add(bond);
}
for (IBond bond : bondsToDelete) clone.removeBond(bond);

// at this point, the ring systems are disconnected components
IAtomContainerSet ringSystems = ConnectivityChecker.partitionIntoMolecules(clone);
for (IAtomContainer ringSystem : ringSystems.atomContainers()) {
if (ringSystem.getAtomCount() < minimumFragmentSize) continue;
hash = Long.toHexString(generator.generate(ringSystem));
hash = generator.generate(ringSystem);
ringMap.put(hash, ringSystem);
if (!fragmentSet.contains(hash)) fragmentSet.add(hash);
}
Expand All @@ -201,7 +222,7 @@ private void run(IAtomContainer atomContainer) throws CDKException {
// now we split this framework and recurse.
assert currentFramework != null;
for (IBond bond : currentFramework.bonds()) {
if (islinker(bond) || isZeroAtomLinker(bond, currentFramework)) {
if (islinker(bond) || isZeroAtomLinker(bond)) {
List<IAtomContainer> candidates = FragmentUtils.splitMolecule(currentFramework, bond);
for (IAtomContainer candidate : candidates) {

Expand All @@ -218,7 +239,7 @@ private void run(IAtomContainer atomContainer) throws CDKException {

// need to keep side chains at one ppint
candidate = removeSideChains(candidate);
hash = Long.toHexString(generator.generate(candidate));
hash = generator.generate(candidate);
if (!fragmentSet.contains(hash) && hasframework(candidate) && candidate.getAtomCount() >= minimumFragmentSize) {
fragmentSet.add(hash);
run(candidate);
Expand Down Expand Up @@ -269,7 +290,8 @@ private void markLinkers(IAtomContainer atomContainer) {
for (IAtom atom1 : atomContainer.atoms()) {
if (atom1.getFlag(CDKConstants.ISINRING) || !(Boolean) atom1.getProperty(IS_CONNECTED_TO_RING)) continue;
for (IAtom atom2 : atomContainer.atoms()) {
if (atom2.getFlag(CDKConstants.ISINRING) || !(Boolean) atom2.getProperty(IS_CONNECTED_TO_RING)) continue;
if (atom2.getFlag(CDKConstants.ISINRING) || !(Boolean) atom2.getProperty(IS_CONNECTED_TO_RING))
continue;

if (atom1.equals(atom2)) continue;

Expand Down Expand Up @@ -300,6 +322,12 @@ private void markSideChains(IAtomContainer atomContainer) {
}
}

private List<String> getSmilesFromAtomContainers(Collection<IAtomContainer> mols) {
List<String> smis = new ArrayList<String>();
for (IAtomContainer mol : mols) smis.add(smigen.createSMILES(mol));
return smis;
}

/**
* This returns the frameworks and ring systems from a Murcko fragmentation.
* <p/>
Expand All @@ -315,8 +343,8 @@ private void markSideChains(IAtomContainer atomContainer) {
@TestMethod("testMF1")
public String[] getFragments() {
List<String> allfrags = new ArrayList<String>();
allfrags.addAll(frameMap.keySet());
allfrags.addAll(ringMap.keySet());
allfrags.addAll(getSmilesFromAtomContainers(frameMap.values()));
allfrags.addAll(getSmilesFromAtomContainers(ringMap.values()));
return allfrags.toArray(new String[]{});
}

Expand All @@ -340,7 +368,7 @@ public IAtomContainer[] getFragmentsAsContainers() {
*/
@TestMethod("testMF1")
public String[] getRingSystems() {
return ringMap.keySet().toArray(new String[]{});
return getSmilesFromAtomContainers(ringMap.values()).toArray(new String[]{});
}

/**
Expand All @@ -360,7 +388,7 @@ public IAtomContainer[] getRingSystemsAsContainers() {
*/
@TestMethod("testMF2,testMF3")
public String[] getFrameworks() {
return frameMap.keySet().toArray(new String[]{});
return getSmilesFromAtomContainers(frameMap.values()).toArray(new String[]{});
}

/**
Expand Down Expand Up @@ -391,8 +419,8 @@ private boolean islinker(IBond bond) {
return islinker(bond.getAtom(0)) || islinker(bond.getAtom(1));
}

private boolean isZeroAtomLinker(IBond bond, IAtomContainer mol) {
boolean isRingBond = (new SpanningTree(mol)).getCyclicFragmentsContainer().contains(bond);
private boolean isZeroAtomLinker(IBond bond) {
boolean isRingBond = bond.getFlag(CDKConstants.ISINRING);
return isring(bond.getAtom(0)) && isring(bond.getAtom(1)) && !isRingBond;
}

Expand All @@ -409,7 +437,7 @@ private boolean hasframework(IAtomContainer atomContainer) {
// in which case, the atoms of the bond are not
// linker atoms, but the bond itself is a (pseudo) linker bond
for (IBond bond : atomContainer.bonds()) {
if (isZeroAtomLinker(bond, atomContainer)) {
if (isZeroAtomLinker(bond)) {
hasLinker = true;
break;
}
Expand Down

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