Standardization and Generation of Parentsfor

Open PHACTS Chemical Registry System

Karen Karapetyan, Valery TkachenkoColin Batchelor, Antony Williams

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

Severity assigned to every validation issue

Filtering by severity and by issues

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)

O–

O

O H

ONa

+

Na

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]

Standardization Dearomatize

Double bond with adjacent wiggly single bond

Fold hydrogen atoms with no up or down bonds

ClCl

Cl

NH 2

O

Cl

N

H

H

Cl

H

Cl

O

Standardization Remove symmetric stereocenters

Turn off chiral flag if no up or down bonds Do Layout

Chiral flag is set

N H 2

NH 2NH 2

N H 2

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

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:closeMatchdul: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:closeMatchcheminf: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;

Fragment

SID 1

SDF1DataSource1Synonym1Synonym2XRef1

SID 2

SDF2DataSource2Synonym1Synonym3XRef2

OPS_ID 1

DepositedSubstances

Parents

Standardized MOLECULE

DataSource1DataSource2Synonym1Synonym2Synonym3XRef1XRef2

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

DataSource3DataSource4Synonym4Synonym5Synonym6XRef3XRef4

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 SolutionNon-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

Thanks

We would appreciate any comments.

For comments or questions emailkarapetyank@rsc.org