public void TestGetBondLength()
{
PharmacophoreAtom patom1 = new PharmacophoreAtom("[CX2]N", "Amine", Vector3.Zero);
PharmacophoreAtom patom2 = new PharmacophoreAtom("c1ccccc1", "Aromatic", new Vector3(1, 1, 1));
PharmacophoreBond pbond = new PharmacophoreBond(patom1, patom2);
Assert.AreEqual(1.732051, pbond.BondLength, 0.00001);
}
public void TestGetterSetter()
{
PharmacophoreAtom patom = new PharmacophoreAtom("[CX2]N", "Amine", Vector3.Zero);
Assert.AreEqual("[CX2]N", patom.Smarts);
patom.Smarts = "[OX2]";
Assert.AreEqual("[OX2]", patom.Smarts);
}
public void TestGetAngle5()
{
PharmacophoreAtom patom1 = new PharmacophoreAtom("[CX2]N", "Amine", new Vector3(1, 1, 1));
PharmacophoreAtom patom2 = new PharmacophoreAtom("c1ccccc1", "Aromatic", Vector3.Zero);
PharmacophoreAtom patom3 = new PharmacophoreAtom("C", "Blah", new Vector3(1, 0, 0));
PharmacophoreAngleBond pbond = new PharmacophoreAngleBond(patom1, patom2, patom3);
Assert.AreEqual(54.7356, pbond.BondLength, 0.0001);
}
private static PharmacophoreAtom NewPCoreAtom(IAtomContainer input, PharmacophoreQueryAtom qatom, string smarts, int[] mapping)
{
var coords = GetEffectiveCoordinates(input, mapping);
var patom = new PharmacophoreAtom(smarts, qatom.Symbol, coords);
// n.b. mapping[] copy is mad by pcore atom
patom.SetMatchingAtoms(mapping);
return(patom);
}
public void TestMatchingAtoms()
{
PharmacophoreAtom patom = new PharmacophoreAtom("[CX2]N", "Amine", Vector3.Zero);
patom.SetMatchingAtoms(new int[] { 1, 4, 5 });
int[] indices = patom.GetMatchingAtoms();
Assert.AreEqual(1, indices[0]);
Assert.AreEqual(4, indices[1]);
Assert.AreEqual(5, indices[2]);
}
public override bool Equals(object o)
{
if (!(o is PharmacophoreAtom))
{
return(false);
}
PharmacophoreAtom that = (PharmacophoreAtom)o;
return(Smarts.Equals(that.Smarts, StringComparison.Ordinal) && Symbol.Equals(that.Symbol, StringComparison.Ordinal) &&
Point3D.Equals(that.Point3D) && Arrays.AreEqual(this.matchingAtoms, that.matchingAtoms));
}
/// <summary>
/// Create a pharmacophore group.
/// </summary>
/// <param name="pharmacophoreAtom">A previously created pharmacophore group</param>
public PharmacophoreAtom(PharmacophoreAtom pharmacophoreAtom)
{
Smarts = pharmacophoreAtom.Smarts;
this.Symbol = pharmacophoreAtom.Symbol;
Point3D = pharmacophoreAtom.Point3D;
if (pharmacophoreAtom.GetMatchingAtoms() != null)
{
var indices = pharmacophoreAtom.GetMatchingAtoms();
matchingAtoms = new int[indices.Length];
Array.Copy(indices, 0, matchingAtoms, 0, indices.Length);
}
}
public void TestMatchedBonds()
{
Assert.IsNotNull(conformers);
// make a query
PharmacophoreQuery query = new PharmacophoreQuery();
PharmacophoreQueryAtom o = new PharmacophoreQueryAtom("D", "[OX1]");
PharmacophoreQueryAtom n1 = new PharmacophoreQueryAtom("A", "[N]");
PharmacophoreQueryAtom n2 = new PharmacophoreQueryAtom("A", "[N]");
query.Atoms.Add(o);
query.Atoms.Add(n1);
query.Atoms.Add(n2);
PharmacophoreQueryBond b1 = new PharmacophoreQueryBond(o, n1, 4.0, 4.5);
PharmacophoreQueryBond b2 = new PharmacophoreQueryBond(o, n2, 4.0, 5.0);
PharmacophoreQueryBond b3 = new PharmacophoreQueryBond(n1, n2, 5.4, 5.8);
query.Bonds.Add(b1);
query.Bonds.Add(b2);
query.Bonds.Add(b3);
IAtomContainer conf1 = conformers[0];
PharmacophoreMatcher matcher = new PharmacophoreMatcher(query);
bool status = matcher.Matches(conf1);
Assert.IsTrue(status);
var bMatches = matcher.GetMatchingPharmacophoreBonds();
Assert.AreEqual(2, bMatches.Count); // 2 since we haven't gotten a unique set
Assert.AreEqual(3, bMatches[0].Count);
PharmacophoreBond pbond = (PharmacophoreBond)BondRef.Deref(bMatches[0][0]);
PharmacophoreAtom patom1 = (PharmacophoreAtom)AtomRef.Deref(pbond.Begin);
PharmacophoreAtom patom2 = (PharmacophoreAtom)AtomRef.Deref(pbond.End);
Assert.AreEqual("D", patom1.Symbol);
Assert.AreEqual("A", patom2.Symbol);
var bondMap = matcher.GetTargetQueryBondMappings();
Assert.AreEqual(2, bondMap.Count);
var mapping = bondMap[0];
// get the 'BondRef' for lookup
IBond value = mapping[bMatches[0][0]];
Assert.AreEqual(b1, value);
}
/// <summary>
/// Performs the pharmacophore matching.
/// </summary>
/// <param name="atomContainer">The target molecule. Must have 3D coordinates</param>
/// <param name="initializeTarget">If <see langword="true"/>, the target molecule specified in the
/// first argument will be analyzed to identify matching pharmacophore groups. If <see langword="false"/>
/// this is not performed. The latter case is only useful when dealing with conformers
/// since for a given molecule, all conformers will have the same pharmacophore groups
/// and only the constraints will change from one conformer to another.</param>
/// <returns><see langword="true"/> is the target molecule contains the query pharmacophore</returns>
/// <exception cref="CDKException">
/// if the query pharmacophore was not set or the query is invalid or if the molecule
/// does not have 3D coordinates</exception>
public bool Matches(IAtomContainer atomContainer, bool initializeTarget)
{
if (!GeometryUtil.Has3DCoordinates(atomContainer))
{
throw new CDKException("Molecule must have 3D coordinates");
}
if (pharmacophoreQuery == null)
{
throw new CDKException("Must set the query pharmacophore before matching");
}
if (!CheckQuery(pharmacophoreQuery))
{
throw new CDKException("A problem in the query. Make sure all pharmacophore groups of the same symbol have the same same SMARTS");
}
var title = atomContainer.Title;
if (initializeTarget)
{
pharmacophoreMolecule = GetPharmacophoreMolecule(atomContainer);
}
else
{
// even though the atoms comprising the pcore groups are
// constant, their coords will differ, so we need to make
// sure we get the latest set of effective coordinates
foreach (var iAtom in pharmacophoreMolecule.Atoms)
{
var patom = PharmacophoreAtom.Get(iAtom);
var tmpList = new List <int>();
foreach (var idx in patom.GetMatchingAtoms())
{
tmpList.Add(idx);
}
var coords = GetEffectiveCoordinates(atomContainer, tmpList);
patom.Point3D = coords;
}
}
if (pharmacophoreMolecule.Atoms.Count < pharmacophoreQuery.Atoms.Count)
{
Debug.WriteLine($"Target [{title}] did not match the query SMARTS. Skipping constraints");
return(false);
}
mappings = Pattern.FindSubstructure(pharmacophoreQuery).MatchAll(pharmacophoreMolecule);
// XXX: doing one search then discarding
return(mappings.AtLeast(1));
}
public void TestMatches()
{
PharmacophoreQueryAtom qatom = new PharmacophoreQueryAtom("aromatic", "c1ccccc1");
PharmacophoreAtom patom1 = new PharmacophoreAtom("c1ccccc1", "aromatic", Vector3.Zero);
PharmacophoreAtom patom2 = new PharmacophoreAtom("c1ccccc1", "hydrophobic", Vector3.Zero);
PharmacophoreAtom patom3 = new PharmacophoreAtom("Cc1ccccc1", "aromatic", Vector3.Zero);
PharmacophoreAtom patom4 = new PharmacophoreAtom("[CX2]N", "amine", Vector3.Zero);
Assert.IsTrue(qatom.Matches(patom1));
Assert.IsFalse(qatom.Matches(patom2));
Assert.IsTrue(qatom.Matches(patom3));
Assert.IsFalse(qatom.Matches(patom4));
}
public void TestMatches()
{
PharmacophoreAtom patom1 = new PharmacophoreAtom("[CX2]N", "Amine", Vector3.Zero);
PharmacophoreAtom patom2 = new PharmacophoreAtom("c1ccccc1", "Aromatic", new Vector3(1, 1, 1));
PharmacophoreBond pbond = new PharmacophoreBond(patom1, patom2);
PharmacophoreQueryAtom qatom1 = new PharmacophoreQueryAtom("Amine", "[CX2]N");
PharmacophoreQueryAtom qatom2 = new PharmacophoreQueryAtom("aromatic", "c1ccccc1");
PharmacophoreQueryBond qbond1 = new PharmacophoreQueryBond(qatom1, qatom2, 1.0, 2.0);
PharmacophoreQueryBond qbond2 = new PharmacophoreQueryBond(qatom1, qatom2, 1.732);
PharmacophoreQueryBond qbond3 = new PharmacophoreQueryBond(qatom1, qatom2, 0.1, 1.0);
Assert.IsTrue(qbond1.Matches(pbond));
Assert.IsTrue(qbond2.Matches(pbond));
Assert.IsFalse(qbond3.Matches(pbond));
}
public void TestMatches()
{
PharmacophoreAtom patom1 = new PharmacophoreAtom("[CX2]N", "Amine", new Vector3(1, 1, 1));
PharmacophoreAtom patom2 = new PharmacophoreAtom("c1ccccc1", "Aromatic", Vector3.Zero);
PharmacophoreAtom patom3 = new PharmacophoreAtom("C", "Blah", new Vector3(1, 0, 0));
PharmacophoreAngleBond pbond = new PharmacophoreAngleBond(patom1, patom2, patom3);
PharmacophoreQueryAtom qatom1 = new PharmacophoreQueryAtom("Amine", "[CX2]N");
PharmacophoreQueryAtom qatom2 = new PharmacophoreQueryAtom("aromatic", "c1ccccc1");
PharmacophoreQueryAtom qatom3 = new PharmacophoreQueryAtom("blah", "C");
PharmacophoreQueryAngleBond qbond1 = new PharmacophoreQueryAngleBond(qatom1, qatom2, qatom3, 54.735);
PharmacophoreQueryAngleBond qbond2 = new PharmacophoreQueryAngleBond(qatom1, qatom2, qatom3, 50, 60);
PharmacophoreQueryAngleBond qbond3 = new PharmacophoreQueryAngleBond(qatom1, qatom2, qatom3, 60, 80);
PharmacophoreQueryBond qbond4 = new PharmacophoreQueryBond(qatom1, qatom2, 1, 2);
Assert.IsTrue(qbond1.Matches(pbond));
Assert.IsTrue(qbond2.Matches(pbond));
Assert.IsFalse(qbond3.Matches(pbond));
Assert.IsFalse(qbond4.Matches(pbond));
}
public void TestEquals()
{
PharmacophoreAtom patom1 = new PharmacophoreAtom("[CX2]N", "Amine", Vector3.Zero);
patom1.SetMatchingAtoms(new int[] { 1, 4, 5 });
PharmacophoreAtom patom2 = new PharmacophoreAtom("[CX2]N", "Amine", Vector3.Zero);
patom2.SetMatchingAtoms(new int[] { 1, 4, 5 });
PharmacophoreAtom patom3 = new PharmacophoreAtom("[CX2]N", "Amine", new Vector3(0, 1, 0));
patom3.SetMatchingAtoms(new int[] { 1, 4, 5 });
PharmacophoreAtom patom4 = new PharmacophoreAtom("[CX2]N", "Amine", Vector3.Zero);
patom4.SetMatchingAtoms(new int[] { 1, 4, 6 });
Assert.AreEqual(patom2, patom1);
Assert.AreNotSame(patom3, patom1);
Assert.AreNotSame(patom4, patom1);
}
/// <summary>
/// Checks whether this query atom matches a target atom.
/// <para>
/// Currently a query pharmacophore atom will match a target pharmacophore group if the
/// symbols of the two groups match. This is based on the assumption that
/// pharmacophore groups with the same symbol will have the same SMARTS
/// pattern.
/// </para>
/// </summary>
/// <param name="atom">A target pharmacophore group</param>
/// <returns>true if the current query group has the same symbol as the target group</returns>
public bool Matches(IAtom atom)
{
var patom = PharmacophoreAtom.Get(atom);
return(patom.Symbol.Equals(Symbol, StringComparison.Ordinal));
}
/// <summary>
/// Create a pharmacophore distance constraint.
/// </summary>
/// <param name="patom1">The first pharmacophore group</param>
/// <param name="patom2">The second pharmacophore group</param>
/// <param name="patom3">The third pharmacophore group</param>
public PharmacophoreAngleBond(PharmacophoreAtom patom1, PharmacophoreAtom patom2, PharmacophoreAtom patom3)
: base(new PharmacophoreAtom[] { patom1, patom2, patom3 })
{
}
/// <summary>
/// Create a pharmacophore distance constraint.
/// </summary>
/// <param name="patom1">The first pharmacophore group</param>
/// <param name="patom2">The second pharmacophore group</param>
public PharmacophoreBond(PharmacophoreAtom patom1, PharmacophoreAtom patom2)
: base(patom1, patom2)
{
}
/// <summary>
/// Convert the input into a pcore molecule.
/// </summary>
/// <param name="input">the compound being converted from</param>
/// <returns>pcore molecule </returns>
/// <exception cref="CDKException">match failed</exception>
private IAtomContainer GetPharmacophoreMolecule(IAtomContainer input)
{
// XXX: prepare query, to be moved
PrepareInput(input);
var pharmacophoreMolecule = input.Builder.NewAtomContainer();
var matched = new HashSet <string>();
var uniqueAtoms = new LinkedHashSet <PharmacophoreAtom>();
Debug.WriteLine($"Converting [{input.Title}] to a pcore molecule");
// lets loop over each pcore query atom
foreach (var atom in pharmacophoreQuery.Atoms)
{
var qatom = (PharmacophoreQueryAtom)atom;
var smarts = qatom.Smarts;
// a pcore query might have multiple instances of a given pcore atom (say
// 2 hydrophobic groups separated by X unit). In such a case we want to find
// the atoms matching the pgroup SMARTS just once, rather than redoing the
// matching for each instance of the pcore query atom.
if (!matched.Add(qatom.Symbol))
{
continue;
}
// see if the smarts for this pcore query atom gets any matches
// in our query molecule. If so, then collect each set of
// matching atoms and for each set make a new pcore atom and
// add it to the pcore atom container object
int count = 0;
foreach (var query in qatom.CompiledSmarts)
{
// create the lazy mappings iterator
var mappings = query.MatchAll(input).GetUniqueAtoms();
foreach (var mapping in mappings)
{
uniqueAtoms.Add(NewPCoreAtom(input, qatom, smarts, mapping));
count++;
}
}
Debug.WriteLine($"\tFound {count} unique matches for {smarts}");
}
pharmacophoreMolecule.SetAtoms(uniqueAtoms.ToArray());
// now that we have added all the pcore atoms to the container
// we need to join all atoms with pcore bonds (i.e. distance constraints)
if (HasDistanceConstraints(pharmacophoreQuery))
{
var npatom = pharmacophoreMolecule.Atoms.Count;
for (int i = 0; i < npatom - 1; i++)
{
for (int j = i + 1; j < npatom; j++)
{
var atom1 = PharmacophoreAtom.Get(pharmacophoreMolecule.Atoms[i]);
var atom2 = PharmacophoreAtom.Get(pharmacophoreMolecule.Atoms[j]);
var bond = new PharmacophoreBond(atom1, atom2);
pharmacophoreMolecule.Bonds.Add(bond);
}
}
}
// if we have angle constraints, generate only the valid
// possible angle relationships, rather than all possible
if (HasAngleConstraints(pharmacophoreQuery))
{
int nangleDefs = 0;
foreach (var bond in pharmacophoreQuery.Bonds)
{
if (!(bond is PharmacophoreQueryAngleBond))
{
continue;
}
var startQAtom = bond.Atoms[0];
var middleQAtom = bond.Atoms[1];
var endQAtom = bond.Atoms[2];
// make a list of the patoms in the target that match
// each type of angle atom
var startl = new List <IAtom>();
var middlel = new List <IAtom>();
var endl = new List <IAtom>();
foreach (var tatom in pharmacophoreMolecule.Atoms)
{
if (tatom.Symbol.Equals(startQAtom.Symbol, StringComparison.Ordinal))
{
startl.Add(tatom);
}
if (tatom.Symbol.Equals(middleQAtom.Symbol, StringComparison.Ordinal))
{
middlel.Add(tatom);
}
if (tatom.Symbol.Equals(endQAtom.Symbol, StringComparison.Ordinal))
{
endl.Add(tatom);
}
}
// now we form the relevant angles, but we will
// have reversed repeats
var tmpl = new List <IAtom[]>();
foreach (var middle in middlel)
{
foreach (var start in startl)
{
if (middle.Equals(start))
{
continue;
}
foreach (var end in endl)
{
if (start.Equals(end) || middle.Equals(end))
{
continue;
}
tmpl.Add(new IAtom[] { start, middle, end });
}
}
}
// now clean up reversed repeats
var unique = new List <IAtom[]>();
for (int i = 0; i < tmpl.Count; i++)
{
var seq1 = tmpl[i];
bool isRepeat = false;
for (int j = 0; j < unique.Count; j++)
{
if (i == j)
{
continue;
}
var seq2 = unique[j];
if (Compares.AreDeepEqual(seq1[1], seq2[1]) && Compares.AreDeepEqual(seq1[0], seq2[2]) && Compares.AreDeepEqual(seq1[2], seq2[0]))
{
isRepeat = true;
}
}
if (!isRepeat)
{
unique.Add(seq1);
}
}
// finally we can add the unique angle to the target
foreach (var seq in unique)
{
var pbond = new PharmacophoreAngleBond(PharmacophoreAtom.Get(seq[0]), PharmacophoreAtom.Get(seq[1]), PharmacophoreAtom.Get(seq[2]));
pharmacophoreMolecule.Bonds.Add(pbond);
nangleDefs++;
}
}
Debug.WriteLine($"Added {nangleDefs} defs to the target pcore molecule");
}
return(pharmacophoreMolecule);
}
