generatefragments.java

化学图形处理软件

/* $Revision: 8718 $ $Author: egonw $ $Date: 2007-08-28 10:22:35 +0200 (Tue, 28 Aug 2007) $
 *
 * Copyright (C) 2005-2007  Christian Hoppe <[e-mail]>
 *
 * Contact: [e-mail]
 *
 * This program is free software; you can redistribute it and/or
 * modify it under the terms of the GNU Lesser General Public License
 * as published by the Free Software Foundation; either version 2.1
 * of the License, or (at your option) any later version.
 * All we ask is that proper credit is given for our work, which includes
 * - but is not limited to - adding the above copyright notice to the beginning
 * of your source code files, and to any copyright notice that you may distribute
 * with programs based on this work.
 *
 * This program is distributed in the hope that it will be useful,
 * but WITHOUT ANY WARRANTY; without even the implied warranty of
 * MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE.  See the
 * GNU Lesser General Public License for more details.
 *
 * You should have received a copy of the GNU Lesser General Public License
 * along with this program; if not, write to the Free Software
 * Foundation, Inc., 51 Franklin St, Fifth Floor, Boston, MA 02110-1301 USA.
 *
 */
package org.openscience.cdk.tools;

import java.util.ArrayList;
import java.util.List;
import java.util.Vector;

import org.openscience.cdk.AtomContainer;
import org.openscience.cdk.CDKConstants;
import org.openscience.cdk.Molecule;
import org.openscience.cdk.exception.NoSuchAtomException;
import org.openscience.cdk.graph.ConnectivityChecker;
import org.openscience.cdk.graph.PathTools;
import org.openscience.cdk.interfaces.IAtom;
import org.openscience.cdk.interfaces.IAtomContainer;
import org.openscience.cdk.interfaces.IMolecule;
import org.openscience.cdk.interfaces.IRingSet;
import org.openscience.cdk.ringsearch.RingPartitioner;
import org.openscience.cdk.ringsearch.SSSRFinder;
import org.openscience.cdk.smiles.SmilesGenerator;

/**
 * Generate ring and Murcko-like fragments.
 * <ul>
 *   <li>ring fragments (largest ringsystems)</li>
 *   <li>Murcko fragments described by Murcko et al. {@cdk.cite MURCKO96}</li>
 * </ul>
 *
 * Linkers include the ring atoms. In CDK notion aromatic atoms are flagged as ISAROMATIC and have small letters in smiles.
 * If you want to create molecules out of these smiles you have to change all the letters to upper ones.
 * For this please use isSmilesToUpperCase() and setSmilesToUpperCase()
 * 
 * <p>Due to some problems with SaturationChecker the SMILES generation might be a problem.
 * When you want to use the get..SmileArray methods please do (that seems to work, refer test 13+14):
 * <pre>
 * HydrogenAdder ha= new HydrogenAdder();
 * ha.addExplicitHydrogensToSatisfyValency(molecule);
 * GenerateFragments gf=new GenerateFragments();
 * gf.generateMurckoFragments(molecule,booelan,booelan);
 * String[] smiles=gf.getMurckoFrameworksAsSmileArray();
 * </pre>
 *
 * @author      chhoppe from EUROSCREEN
 * @cdk.created 2006-3-23
 * @cdk.module  experimental
 * @cdk.keyword Murcko fragments
 * 
 **/
public class GenerateFragments {
	
	private LoggingTool logger;
	
	private List murckoFragments =null;
	private List ringFragments=null;
	private List linkerFragments=null;
	private IRingSet ringSetsMolecule=null;
	private boolean sidechainHetatoms=true;
	private boolean exocyclicDoubleBonds=true;
	private boolean smilesToUpperCase=false;
	//private IChemObjectBuilder builder;
	
	public GenerateFragments() {
		logger = new LoggingTool(this);
    }
	
	/**
	 * generates ring fragments from SSSR and RingPartitioner method
	 * @param molecule
	 * void
	 */
	public void generateRingFragments(IMolecule molecule){
		this.ringFragments= new ArrayList();
		this.ringSetsMolecule = new SSSRFinder(molecule).findSSSR();
		if (this.ringSetsMolecule.getAtomContainerCount() > 0) {
			this.ringFragments=RingPartitioner.partitionRings(ringSetsMolecule);
		}
	}
	
	
	/**
	 * generates Murcko fragments takes two parameters
	 * @param molecule	the molecule
	 * @param sidechainHetatoms	boolean if sidchain hetero atoms should be included (true)
	 * @param exocyclicDoubleBonds boolean if bonds with order >1 should be included on ring systems and linkers
	 * @param minimumRingSize int indicates the minimum ring size as to considered as fragment (ringSize<minimimRingSize)
	 * return	void
	 */
	public void generateMurckoFragments(IMolecule molecule, boolean sidechainHetatoms,boolean exocyclicDoubleBonds, int minimumRingSize) throws org.openscience.cdk.exception.CDKException{
		//logger.debug("****** generatemurckoFragments *******");
		//VARIABLES
		this.murckoFragments =new Vector();
		this.linkerFragments=new Vector();
		this.sidechainHetatoms=sidechainHetatoms;
		this.exocyclicDoubleBonds=exocyclicDoubleBonds;
					
		IAtom firstRingAtom = null;	
		IAtom secondRingAtom = null;	
		IAtomContainer firstRingAtomContainer=null;
		IAtomContainer secondRingAtomContainer=null;
		IAtomContainer firstRingSubstituents=null;
		IAtomContainer secondRingSubstituents=null;
		IAtomContainer path=null;
		IMolecule murckoFragment=null;
		IMolecule linkerFragment=null;
		List tmpRingFragments=new Vector();
		
		//Initialize
		generateRingFragments(molecule);
		
		for (int i = 0; i < molecule.getAtomCount(); i++) {
			molecule.getAtom(i).setFlag(CDKConstants.ISINRING, false);
		}
				
		//logger.debug("Number of RingSystems:"+this.ringFragments.size());
		for (int f = 0; f < this.ringFragments.size(); f++) {
			firstRingAtomContainer = molecule.getBuilder().newAtomContainer();
			IRingSet ringSet = (IRingSet)this.ringFragments.get(f);
			for (int i=0;i<ringSet.getAtomContainerCount();i++) {
				firstRingAtomContainer.add(ringSet.getAtomContainer(i));
			}
			
			if (firstRingAtomContainer.getAtomCount()>=minimumRingSize){
				tmpRingFragments.add(firstRingAtomContainer);
				for (int g = 0; g < firstRingAtomContainer.getAtomCount(); g++) {
					molecule.getAtom(molecule.getAtomNumber(firstRingAtomContainer.getAtom(g))).setFlag(CDKConstants.ISINRING, true);
				}
				
			}
		}

//		START
		//logger.debug("Number of RingSystems:"+tmpRingFragments.size());
		if (tmpRingFragments.size() > 1) {
			//go through all ringsystems
			//for (int f = 0; f < this.ringFragments.size()-1; f++) {
			for (int f = 0; f < tmpRingFragments.size()-1; f++) {	
			//firstRingAtomContainer = RingSetManipulator.getAllInOneContainer((IRingSet) this.ringFragments.get(f));
				firstRingAtomContainer = (IAtomContainer)tmpRingFragments.get(f);
				//for (int g = f+1; g < this.ringFragments.size(); g++) {
					//secondRingAtomContainer = RingSetManipulator.getAllInOneContainer((IRingSet) this.ringFragments.get(g));
				for (int g = f+1; g < tmpRingFragments.size(); g++) {
					secondRingAtomContainer = (IAtomContainer)tmpRingFragments.get(g);
					for (int h = 0; h < firstRingAtomContainer.getAtomCount(); h++){
						firstRingAtom=firstRingAtomContainer.getAtom(h);
						firstRingSubstituents=getPossibleLinkerSubstituents(firstRingAtom,molecule,firstRingAtomContainer);
						if (firstRingSubstituents.getAtomCount()>0){
							//go through substituents of first ring
							for (int i = 0; i < firstRingSubstituents.getAtomCount(); i++){
//								logger.debug("First Ring Sub is in RING");
//								//check for ring-ring system
								//Is a zero-atom linker
								if (firstRingSubstituents.getAtom(i).getFlag(CDKConstants.ISINRING) && secondRingAtomContainer.contains(firstRingSubstituents.getAtom(i))){
									//logger.debug("\tFound a ring-ring System");
									murckoFragment=new Molecule();
									
									murckoFragment=addFragments(firstRingAtomContainer,murckoFragment,molecule);
									murckoFragment=addFragments(secondRingAtomContainer,murckoFragment,molecule);
									murckoFragment=addFragmentBonds(murckoFragment,molecule);
									
									linkerFragment=new Molecule();
									linkerFragment.addAtom(firstRingAtom);
									linkerFragment.addAtom(firstRingSubstituents.getAtom(i));
									linkerFragment=addFragmentBonds(linkerFragment, molecule);
									
									this.linkerFragments.add(linkerFragment);
									this.murckoFragments.add(murckoFragment);
									//logger.debug("MFragment:"+murckoFragment.getAtomCount()+" CC:"+ConnectivityChecker.isConnected(murckoFragment));
									//logger.debug(murckoFragment.toString());
									//logger.debug("\tADD MURCKOFRAGMENT");
									break;
								}
//								compare to substituents of second ring
								for (int j = 0; j < secondRingAtomContainer.getAtomCount(); j++){
									secondRingAtom=secondRingAtomContainer.getAtom(j);
									secondRingSubstituents=getPossibleLinkerSubstituents(secondRingAtom,molecule,secondRingAtomContainer);
									if (secondRingSubstituents.getAtomCount()>0){
										//go through substituents of second ring
										for (int k = 0; k < secondRingSubstituents.getAtomCount(); k++){//For-k
											
											//logger.debug("First Ring Size:"+firstRingAtomContainer.getAtomCount()+" 2.Ring Size:"+secondRingAtomContainer.getAtomCount());
											//logger.debug(f+".ringSub:"+molecule.getAtomNumber(firstRingSubstituents.getAtomAt(i))+" Sym:"+firstRingSubstituents.getAtomAt(i).getSymbol()+" "+g+".ringSub:"+molecule.getAtomNumber(secondRingSubstituents.getAtomAt(k)));
											path=new AtomContainer();
											try {
												resetFlags(molecule);
												PathTools.depthFirstTargetSearch(molecule,firstRingSubstituents.getAtom(i),secondRingSubstituents.getAtom(k),path);
												/*logger.debug("\tPATHSIZE:"+path.getAtomCount());
												logger.debug("\tFIRST PATHATOM:"+molecule.getAtomNumber(path.getAtomAt(0)));
												try{
													logger.debug("\tLAST PATHATOM:"+molecule.getAtomNumber(path.getAtomAt(path.getAtomCount()-1)));
												}catch(Exception eS){
													logger.debug("\tNO LAST PATHATOM");
												}*/
												
												if (firstRingSubstituents.getAtom(i)==secondRingSubstituents.getAtom(k)){
													//logger.debug("\tSubstituents are equal");
													path.addAtom(firstRingSubstituents.getAtom(i));
												}
												
												//Check Path, direct connection between the substituents ->linker
												if ((checkPath(firstRingAtom, secondRingAtom, path) && path.getAtomCount()>0)){
													murckoFragment=new Molecule();
													
													//add both root atoms to path
													if (!path.contains(firstRingSubstituents.getAtom(i))){
														path.addAtom(firstRingSubstituents.getAtom(i));
													}
													if (!path.contains(secondRingSubstituents.getAtom(i))){
														path.addAtom(secondRingSubstituents.getAtom(i));
													}
//													//add both ring atoms to path
													//if (!path.contains(firstRingAtom)){
													//	path.addAtom(firstRingAtom);
													//}
													//if (!path.contains(secondRingAtom)){
													//	path.addAtom(secondRingAtom);
													//}
													//1. add path
													//2. add rings  
													//3. connect ring atoms to path
													murckoFragment=addPathFragments(path,murckoFragment,molecule);
													linkerFragment=new Molecule(murckoFragment);
													if (!linkerFragment.contains(firstRingAtom)){
														linkerFragment.addAtom(firstRingAtom);
													}
													if (!linkerFragment.contains(secondRingAtom)){
														linkerFragment.addAtom(secondRingAtom);
													}													
													linkerFragment=addFragmentBonds(linkerFragment, molecule);
													murckoFragment=addFragments(firstRingAtomContainer,murckoFragment,molecule);
													murckoFragment=addFragments(secondRingAtomContainer,murckoFragment,molecule);
													
													murckoFragment=addFragmentBonds(murckoFragment,molecule);
																																																		
													this.linkerFragments.add(linkerFragment);
													this.murckoFragments.add(murckoFragment);
													//logger.debug("\tADD MURCKOFRAGMENT");
												}else{
													//logger.debug("\tEND PATH");
												}
												
												
											} catch (NoSuchAtomException e) {
												// TODO Auto-generated catch block
												e.printStackTrace();
											}//catch
										}//For-k
									}//if 2.ring sub
								}//For-j
							}//For-i
						}//if 1.ring sub
					}//For-h
				}//For-g				
			}//For-f				
		}else if (tmpRingFragments.size() ==1){
			//logger.debug("Number of RingSystems is 1");
			murckoFragment=new Molecule();
			murckoFragment=addFragments((IRingSet) this.ringFragments.get(0),murckoFragment,molecule);
			murckoFragment=addFragmentBonds(murckoFragment,molecule);
			this.murckoFragments.add(murckoFragment);
		}
		
	}