successfully differentiate between CV fragments that have the same

SMILES but different R-Groups/attachment points
ncats · Jan 31, 2025 · 0c0b7aa · 0c0b7aa
1 parent 30524ed
commit 0c0b7aa
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Showing 3 changed files with 54 additions and 9 deletions.
diff --git a/gsrs-module-substance-example/src/test/java/example/chem/VocabFragmentCleanupTest.java b/gsrs-module-substance-example/src/test/java/example/chem/VocabFragmentCleanupTest.java
@@ -224,6 +224,22 @@ void testHaveDifferentHashes() {
         Assertions.assertNotEquals(hash1, hash3);
     }
 
+    @Test
+    void testHaveDifferentHashes2() {
+        FragmentVocabularyTerm fragmentVocabularyTerm1 = new FragmentVocabularyTerm();
+        fragmentVocabularyTerm1.setFragmentStructure("[*]OC[C@@](O[C@@H]([*])2)([C@H]([C@H]21)O[*])CO1 |$_R92;;;;;;_R90;;;;_R91;;;;$|");
+        fragmentVocabularyTerm1.setSimplifiedStructure("[*]OC[C@@](O[C@@H]([*])2)([C@H]([C@H]21)O[*])CO1 |$_R92;;;;;;_R90;;;;_R91;;;;$|");
+        fragmentVocabularyTerm1.setValue("iR");
+        String hash1= CVFragmentStructureValidator.getHash(fragmentVocabularyTerm1).get();
+
+        FragmentVocabularyTerm fragmentVocabularyTerm3 = new FragmentVocabularyTerm();
+        fragmentVocabularyTerm3.setFragmentStructure("[*]OC[C@@]12CO[C@@H]([C@H]([*])O1)[C@@H]2O[*] |$_R91;;;;;;;;_R90;;;;_R92$|");
+        fragmentVocabularyTerm3.setSimplifiedStructure("[*]OC[C@@]12CO[C@@H]([C@H]([*])O1)[C@@H]2O[*] |$_R91;;;;;;;;_R90;;;;_R92$|");
+        fragmentVocabularyTerm3.setValue("LR");
+        String hash3 = CVFragmentStructureValidator.getHash(fragmentVocabularyTerm3).get();
+        Assertions.assertNotEquals(hash1, hash3);
+    }
+
     private String getInChiKey(String smiles) throws IOException {
         Chemical chem = Chemical.parse(smiles);
         String inChIKey = chem.toInchi().getKey();

diff --git a/gsrs-module-substances-core/src/main/java/ix/core/chem/Chem.java b/gsrs-module-substances-core/src/main/java/ix/core/chem/Chem.java
@@ -21,6 +21,9 @@
 public class Chem {
     private Chem () {}
 
+    public static final String WILDCARD_SUBSTITUTION_ATOM = "He";
+    public static final Integer WILDCARD_SUBSTITUTION_ATOM_NUMBER = 2;
+
     public static void setFormula (Structure struc) {
         try {
             struc.formula = formula (struc.toChemical(false));
@@ -32,20 +35,14 @@ public static void setFormula (Structure struc) {
 
     public static Chemical RemoveQueryFeaturesForPseudoInChI(Chemical c) {
         Chemical chemicalToUse = c;
-        /*try {
-            log.trace("RemoveQueryFeaturesForPseudoInChI processing molfile c {}", c.toMol());
-        } catch (IOException e) {
-            log.error("Error generating mol from Chemical");
-        }*/
         if(c.hasQueryAtoms() || c.atoms().filter(at->("A".equals(at.getSymbol()) || "*".equals(at.getSymbol()) || "R".equals(at.getSymbol()))).count()>0){
             chemicalToUse = c.copy();
             chemicalToUse.atoms()
                     .filter(at-> at.getSymbol() == null || "A".equals(at.getSymbol()) || "*".equals(at.getSymbol())
                             || "R".equals(at.getSymbol()))//isQueryAtom returns true
                     .forEach(a->{
-                        a.setAtomicNumber(2);
-                        //verify that this is setting a symbol as well
-                        a.setAlias("He");
+                        a.setAtomicNumber(WILDCARD_SUBSTITUTION_ATOM_NUMBER);
+                        a.setAlias(WILDCARD_SUBSTITUTION_ATOM);
                         a.setMassNumber(6);
                     });
         }

diff --git a/...core/src/main/java/ix/ginas/utils/validation/validators/CVFragmentStructureValidator.java b/...core/src/main/java/ix/ginas/utils/validation/validators/CVFragmentStructureValidator.java
@@ -31,7 +31,9 @@
 
 @Slf4j
 public class CVFragmentStructureValidator extends AbstractValidatorPlugin<ControlledVocabulary> {
-
+
+	private final static int R_GROUP_ADJUSTMENT = 87;
+
 	private class FragmentChanges{
 
 		private List<FragmentVocabularyTerm> addedTerms = new ArrayList<FragmentVocabularyTerm>();
@@ -75,6 +77,10 @@ public void validate(ControlledVocabulary newCV, ControlledVocabulary oldCV, Val
 
 	public static Optional<String> getHash(FragmentVocabularyTerm term) {
 		try {
+			Optional<String> inchiKeyOne= getInchiKeyFromComplexSmiles(term.getFragmentStructure());
+			if(inchiKeyOne.isPresent()) {
+				return inchiKeyOne;
+			}
 			String inputStructure = term.getFragmentStructure().split(" ")[0];
 			Chemical chem = Chemical.parse(inputStructure);
 			//see if we get a good result without changing the structure
@@ -101,6 +107,32 @@ private static Optional<String> getInitialHash(Chemical chem) {
 		}
 	}
 
+	//input 'complex' because it contains both a simple SMILES string and a set of R-Group designations.
+	// for example, [*]OC[C@@]12CO[C@@H]([C@H]([*])O1)[C@@H]2O[*] |$_R91;;;;;;;;_R90;;;;_R92$|
+	private static Optional<String> getInchiKeyFromComplexSmiles(String complexInput) {
+        Chemical initiallyParsedChemical;
+        try {
+            initiallyParsedChemical = Chemical.parse(complexInput);
+	       	initiallyParsedChemical.atoms()
+				.filter(at->at.getRGroupIndex().isPresent() && at.getRGroupIndex().getAsInt() >0)
+				.forEach(at->{
+					///Subtracting this number from an RGroup index will give us a mass number that InChI can use to
+					// differentiate atoms.  When the mass number is too high, InChI ignores it.
+					at.setMassNumber( Math.max(0, at.getRGroupIndex().getAsInt()- R_GROUP_ADJUSTMENT));
+					log.warn("r group: {}", at.getRGroupIndex().getAsInt());
+					at.setAlias(Chem.WILDCARD_SUBSTITUTION_ATOM);
+					at.setAtomicNumber(Chem.WILDCARD_SUBSTITUTION_ATOM_NUMBER);
+					at.setRGroup(0);
+				});
+
+			Chemical transformedChemical= Chemical.parse(initiallyParsedChemical.toSmiles());
+			return Optional.of(transformedChemical.toInchi().getKey());
+		} catch (IOException e) {
+			log.info("in transformComplexSmiles, error parsing input {}", complexInput);
+			return Optional.empty();
+		}
+
+	}
 	private void chemicalValidation(FragmentVocabularyTerm term, Map<String,List<String>> lookup, ValidatorCallback callback) {
 
 		String fragmentStructure = term.getFragmentStructure().trim();