1. Validation and Standardization of Molecular Structures in General and Sugars in Particular: a Case Study Colin Batchelor, Ken Karapetyan, Valery Tkachenko, Antony Williams 6th Joint Sheffield Conference on Chemoinformatics 2013-07-24

2. Overview Open PHACTS and chemical validation and standardization RDF for chemoinformatics calculations General case study: ChEMBL and DrugBank Sugar case study: Perspective perception

3. Overview Open PHACTS and chemical validation and standardization RDF for chemoinformatics calculations General case study: ChEMBL and DrugBank Sugar case study: Perspective perception

4. Who is involved?28 Consortium Members>45 Associated Partners 3-year European project funded by: European Pharmaceutical Industry Innovative Medicines Initiative Open PHACTS API Applications using the Open PHACTS API dev.openphacts.org Explorer www.openphacts.org Twitter: @open_phacts

5. How do we fit in? We integrate and standardize the chemical compound collection underpinning Open PHACTS and provide regular updates and on- going data curation. The validation and standardization rules have been derived from the FDA structure guidelines and have been changed for consistency and input from members of EFPIA.

6. Open PHACTS provides an integrated platform of publicly available pharmacological and physicochemical data ” “ Data accessible via: Free application programming interface (API) dev.openphacts.org Third-party applications built to use the API Open PHACTS app ecosystem

7. How does Open PHACTS work?

8. Currently integrated databases DatabaseMillions of triples ACD Labs / ChemSpider161.3 ChEBI0.9 ChEMBL146.1 ConceptWiki3.7 DrugBank0.5 Enzyme0.1 Gene Ontology0.9 SwissProt156.6 WikiPathways0.1 TOTAL470.2

9. CVSP and the OPS CRS Standardization workflows (CVSP, FDA, OPS, custom) using modules such as: SMIRKS transformations layout (GGA) canonical tautomers (ChemAxon) sugar interpretation (RSC)

10. Overview Open PHACTS and chemical validation and standardization RDF for chemoinformatics calculations General case study: ChEMBL and DrugBank Sugar case study: Perspective perception

11. RDF and Open PHACTS The underlying language of Open PHACTS is RDF. There are few constraints as such, only guidelines for which classes of identifier to use and accounts of best practice. This RDF goes into the data cache and we access the results through user interfaces built on RESTful JSON web services.

12. What does RDF look like? In the Turtle format below, each line is a triple, in which a binary predicate links a subject and an object. :CSID1execution obo:OBO_0000299 :CSID1prop11. :CSID1prop11 obo:IAO_0000136 ops:OPS1. :CSID1prop11 rdf:type cheminf:CHEMINF_000349. :CSID1prop11 qudt:numericValue "1.049E-17"^^xsd:double. :CSID1prop11 qudt:unit obo:UO_0000324. There is also RDF/XML, which is less human- readable.

13. Royal Society of Chemistry data in Open PHACTS 1.Molecule synonyms and identifiers 2.Linksets between ChEBI, ChEMBL, DrugBank and OPS identifiers 3.Molecule–molecule relations (“parent– child”) of interest for drug discovery 4.Calculated physicochemical properties for compounds (both molecular and macroscopic)

14. Royal Society of Chemistry data in Open PHACTS 1.Molecule synonyms and identifiers 2.Linksets between ChEBI, ChEMBL, DrugBank and OPS identifiers 3.Molecule–molecule relations (“parent– child”) of interest for drug discovery 4.Calculated physicochemical properties for compounds (both molecular and macroscopic)

15. Calculated physicochemical properties (ACD 12.0) log P log D (at pH 5.5, at pH 7.4) bioconcentration factor K OC (at pH 5.5, at pH 7.4) index of refraction polar surface area molar refractivity molar volume polarizability surface tension density at STP boiling point at 1 atm flash point at 1 atm enthalpy of vaporization at STP vapour pressure at STP

16. RDF for calculated properties: vocabularies Two dozen calculated properties for each of >10 6 molecules. CHEMINF ontology for kinds of calculation and chemical data QUDT for results OPS IDs for molecules OBI and IAO to connect calculations to results

17. RDF for calculated properties: schema benzene’s connection table OPS benzene calculation result QUDT dimensionless quantity “2.17”^^xsd:float IAO is about OBI has specified output OBI has specified input QUDT has value QUDT has standard uncertainty QUDT has unit CHEMINF calculated log P rdf:type CHEMINF connection table rdf:type “0.234”^^xsd:float calculation process CHEMINF execution of ACD/Labs PhysChem software library version 12.01 rdf:type

18. Overview Open PHACTS and chemical validation and standardization RDF for chemoinformatics calculations General case study: ChEMBL and DrugBank Sugar case study: Perspective perception

19. ChEMBL and DrugBank analysed Taking ChEMBL 16 (http://www.ebi.ac.uk/chembl/) which contains 1 295 510 distinct molecules, CVSP found something to say about 456 250 of them (35%). DrugBank 3.0 (http://www.drugbank.ca/) contains 6510 distinct molecules of which CVSP has found something to say about 662 of them (10%) (We haven’t done all of CS yet; we will.)

20. ChEMBLDrugBank Potentially serious things 142181.09%2023.10%Not an overall neutral system 4850.04%210.32%Forbidden-valence atoms 44—0—Has adjacent atoms with like charges 4—0—Has more than one radical centre

21. ChEMBLDrugBank Aesthetics 572754.42%701.08 % Uneven-length bonds 257361.99%781.20 % Congested layout 236221.82%240.37 % Containing not-quite-linear cyano groups 1670.01%1—Zero-dimensional structures 700.01%0—Containing not-quite-linear isocyano groups

22. ChEMBLDrugBank Artwork molecules 00Cyclobutane 80Ethane molecules in the structure 60Sulfur atoms with no explicit bonds 40Boron atoms with no explicit bonds 10Ethyne molecule (in the ChEMBL case it actually is acetylene) 30Stray methane molecules

23. ChEMBLDrugBank FDA tautomer and metal rules 175081.35%801.29%In enol form (or chalcogenoenol form) 95260.74%40.07%N=C–OH tautomer of a carbonyl compound 2—1—Nitroso-form oximes 11040.09%6 Metal–nitrogen bond 8450.06%100.15%Non-metal–transition-metal bond 4320.03%100.15%Metal–oxygen bond 3—2—Aluminium–non-metal bond 2—0—Metal–fluorine bond

24. ChEMBLDrugBank Stereochemistry 18574214.3%390.60%G2-4: Has a single unknown stereocentre and no defined stereocentres: probably a racemate 685725.3%130.20%G2-42 Has more than one unknown stereocentre and no defined stereocentres: probably problematic. Could indicate relative stereochemistry? 365722.8%270.44%G2-44 At least one defined stereocentre, and one is stereocentre undefined or unknown: probably an epimer or mixture of anomers 260762.0%110.17%G2-46 Has more than one unknown stereocentre and more than one defined stereocentre – probably problematic again 231131.8%130.20%Unknown double bond arrangement 8830.1%1—At least one ring containing stereobonds

25. Overview Open PHACTS and chemical validation and standardization RDF for chemoinformatics calculations General case study: ChEMBL Sugar case study: Perspective perception

26. Sugar depiction challenges Stereochemistry not stored in V2000 format (though present in.cdx).

27. Consequences

28. ChEMBL (19275) DrugBank (153) Sugar questions 535927.8%13890.2%At least one L-pyranose ring (often antibiotics contain these) 474824.6%0—At least one perspective chair 4162.16%0—At least one Haworth ring 520.03%0—At least one perspective boat or twist boat

29. Sugar ring redepiction algorithm 1.Identify perspective conformation (boat, chair, Haworth) 2.Determine perspective stereo 3.Assign wedge or hash to bonds accordingly 4.Reconstruct sugar ring so as to minimize disruption to the rest of molecule 5.Tidy

32. Take the x-axis as parallel to the line through the top two chair atoms or through the bottom two chair atoms. Δy positive: wedge Δy negative: hash Then remap chair to homotropous hexagon.

34. In the boat case, the substituent further up the page is the wedge, while the one further down the page is the hash, regardless of whether bridgehead or not.

35. Depiction 1.Identify mean bond length and chair centroid. 2.Snap ring atoms to a regular-hexagonal grid. 3.Remove superfluous hydrogen atoms. 4.Only mark stereo on a single substituent if they are paired (cf. Grice).

36. Tidying: desiderata Different problem from structure layout in general. The structure we end up with is, in many important respects, fine. Preserve drawing conventions—aglycones being on the top right hand side.

37. Next steps Stable user-facing URI for CVSP (currently http://cvsp.beta.rsc-us.org/, but subject to change) Apply CVSP to all of ChemSpider. Investigate fused rings.

38. Acknowledgements In particular, Jon Steele (RSC) David Sharpe (RSC) John Blunt (Canterbury, NZ)

39. Any questions? batchelorc@rsc.org @documentvector