The document describes standards and processes for generating parent structures from chemical registry data. It outlines validation checks performed on chemical structures and issues assigned severity levels. Standardization procedures are described, including disconnecting certain atoms from metals, ionizing acids, dearomatizing structures, and removing chiral flags and stereocenters in some cases. Parent structures are generated by applying different modifications like making structures insensitive to isotopes, stereo, or tautomers. Primary compound keys may be standard InChI or absolute SMILES strings, but a non-standard InChI approach is proposed to better distinguish stereo and tautomers. Feedback is requested to improve the chemical structure standardization and parenting procedures.

1. Standardization and Generation of Parents
for
Open PHACTS Chemical Registry System
Karen Karapetyan, Valery Tkachenko
Colin Batchelor, Antony Williams

2. Validation checks
 Correct file format (SDF, MOL, CDX, etc)
 “Valid” chemical structure
 Valid atoms (not query atoms)
 Valid bonds
 Valid valences
 Valid charges
 SP3 stereo
 Synonyms
 Names (name to structure)
 SMILES, InChIs (SMILES/InChI to structure)
 XRefs

3. Severity assigned to every validation issue

4. Filtering by severity and by issues

5. Standardization – Organometallics/Salts
 Always disconnect N, O, and F from metals:
 Disconnect nonmetals (except N,O,F) with transition metals (except Hg)
 Ionize free metal with carboxylic acid (Metals of Group I and II)

6. Standardization SMIRKS
(based on InChI normalization and on FDA SRS)
Examples of InChI normalization
 [*;H+:1]>>[*;H:1]
 [O,S,Se,Te:1]=[O+,S+,Se+,Te+:2][C-;v3:3]
>>[O,S,Se,Te:1]=[O,S,Se,Te:2]=[C:3]
 [N-,P-,As-,Sb-:1]=[C+;v3:2]>>[N,P,As,Sb:1]#[C:2]
Examples of FDA SRS rules
 [n:1]=[O:2]>>[n+:1][O-:2]
 [*:1]=[N:2]#[N:3]>>[*:1]=[N+:2]=[N-:3]
 [N+0;H3:1].[C:3](=[O:4])[O:5][H:6]>>[N+1;H4:1].[C:3](=[O:4])[O-:5]
 Thiopurine
[H:1][S:2][c:3]1[n:8][c:7]([H,*:13])[n:6][c:5]2[c:4]1[n:11][c:10]([H,*:12])[n:9]2>>[
H:1][N:8]1[C:7]([H,*:13])=[N:6][C:5]2=[C:4]([N:11]=[C:10]([H,*:12])[N:9]2)[C:3]
1=[S:2]

7. Standardization
 Dearomatize
 Double bond with adjacent wiggly single bond
 Fold hydrogen atoms with no up or down bonds

8. Standardization
 Remove symmetric stereocenters
 Turn off chiral flag if no up or down bonds
 Do Layout
Chiral flag is set

9. Standardization – partially ionized acids
(move proton from strong acids to a weaker)

10. For each Compound parent generation is attempted
“Tautomerism in large databases”, Sitzmann and others,
J.Comput Aided Mol Des (2010)
Parent Description RDF
Charge-Unsensitive An attempt is made to neutralize ionized acids
and bases. Envisioned to be an ongoing
improvement while new cases appear.
void:linkPredicate skos:closeMatch
dul:expresses cheminf:CHEMINF_000460;
Isotope-Unsensitive Isotopes replaced by common weight void:linkPredicate skos:closeMatch;
dul:expresses cheminf:CHEMINF_000459
Stereo-Unsensitive SP3 and double bond stereo removed void:linkPredicate skos:closeMatch
cheminf:CHEMINF_000456
Tautomer-
Unsensitive
Tautomer canonicalization is attempting to
generate a canonical tautomer
void:linkPredicate skos:closeMatch;
dul:expresses cheminf:CHEMINF_000486;
Super Parent Super parent is generated by applying
modifications of all of the above
void:linkPredicate skos:broadMatch;
dul:expresses cheminf:CHEMINF_000458;

11. Fragment
SID 1
SDF1
DataSource1
Synonym1
Synonym2
XRef1
SID 2
SDF2
DataSource2
Synonym1
Synonym3
XRef2
OPS_ID 1
Deposited
Substances
Parents
Standardized
MOLECULE
DataSource1
DataSource2
Synonym1
Synonym2
Synonym3
XRef1
XRef2
Charge Parent (OPS_ID 6)
Isotope Parent (OPS_ID 4)
Stereo Parent (OPS_ID 3)
Tautomer Parent (OPS_ID 5)
Super Parent (OPS_ID 7)
Compounds
OPS_ID 2
Standardized
MOL
DataSource3
DataSource4
Synonym4
Synonym5
Synonym6
XRef3
XRef4

13. What do we use as chemical identity of the standardized records
(primary compound key)?
• Standard InChI/InChIKey (currently used ChemSpider)
• Absolute smiles (isomeric canonical)
Drawbacks
• SMILES – can be too long; no accepted standard; needs to be hashed
• Standard InChI
• does not distinguish between undefined and unknown stereo
• by default standard InChI does some basic tautomer canonicalization
(not needed in new model)
• By default assumes absolute stereo
Proposed Solution
Non-standard InChI with options: SUU SLUUD FixedH SUCF
• much more sensitive to stereo description
• Fixes mobile hydrogens (so tautomers could be distinguished)
• Handles “AND-ed” relative stereo

14. Thanks
We would appreciate any comments.
For comments or questions email
karapetyank@rsc.org