20130724 cisrg sugars_batchelor

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

Overview

Open PHACTS and chemical validation and standardizationRDF for chemoinformatics calculationsGeneral case study: ChEMBL and DrugBankSugar case study: Perspective perception

Overview


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

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.

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

How does Open PHACTS work?

Currently integrated databases

Database Millions of triples

ACD Labs / ChemSpider 161.3ChEBI 0.9ChEMBL 146.1ConceptWiki 3.7DrugBank 0.5Enzyme 0.1Gene Ontology 0.9SwissProt 156.6WikiPathways 0.1TOTAL 470.2

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)

Overview


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.

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.

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)

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)

Calculated physicochemical properties (ACD 12.0)

log P log D (at pH 5.5, at pH 7.4) bioconcentration factor KOC (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

RDF for calculated properties:vocabularies

Two dozen calculated properties for each of >106 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

RDF for calculated properties:schema

benzene’s connection table

OPSbenzene

calculation result

QUDTdimensionless

quantity

“2.17”^^xsd:float

IAOis about

OBIhas specified

output

OBIhas specified

input

QUDThas value

QUDThas standard uncertainty

QUDThas unit

CHEMINFcalculated log P

rdf:type

CHEMINFconnection table

rdf:type

“0.234”^^xsd:float

calculation process

CHEMINFexecution of ACD/Labs

PhysChem software library version 12.01

rdf:type

Overview


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.)

ChEMBL DrugBank

Potentially serious things

14218 1.09% 202 3.10% Not an overall neutral system

485 0.04% 21 0.32% Forbidden-valence atoms

44 — 0 — Has adjacent atoms with like charges

4 — 0 — Has more than one radical centre

ChEMBL DrugBank

Aesthetics

57275 4.42% 70 1.08%

Uneven-length bonds

25736 1.99% 78 1.20%

Congested layout

23622 1.82% 24 0.37%

Containing not-quite-linear cyano groups

167 0.01% 1 — Zero-dimensional structures

70 0.01% 0 — Containing not-quite-linear isocyano groups

ChEMBL DrugBank

Artwork molecules

0 0 Cyclobutane

8 0 Ethane molecules in the structure

6 0 Sulfur atoms with no explicit bonds

4 0 Boron atoms with no explicit bonds

1 0 Ethyne molecule(in the ChEMBL case it actually is acetylene)

3 0 Stray methane molecules

ChEMBL DrugBank

FDA tautomer and metal rules

17508 1.35% 80 1.29% In enol form (or chalcogenoenol form)

9526 0.74% 4 0.07% N=C–OH tautomer of a carbonyl compound

2 — 1 — Nitroso-form oximes

1104 0.09% 6 0.09% Metal–nitrogen bond

845 0.06% 10 0.15% Non-metal–transition-metal bond

432 0.03% 10 0.15% Metal–oxygen bond

3 — 2 — Aluminium–non-metal bond

2 — 0 — Metal–fluorine bond

ChEMBL DrugBank

Stereochemistry

185742 14.3% 39 0.60% G2-4: Has a single unknown stereocentre and no defined stereocentres: probably a racemate

68572 5.3% 13 0.20% G2-42 Has more than one unknown stereocentre and no defined stereocentres: probably problematic. Could indicate relative stereochemistry?

36572 2.8% 27 0.44% G2-44 At least one defined stereocentre, and one is stereocentre undefined or unknown: probably an epimer or mixture of anomers

26076 2.0% 11 0.17% G2-46 Has more than one unknown stereocentre and more than one defined stereocentre – probably problematic again

23113 1.8% 13 0.20% Unknown double bond arrangement

883 0.1% 1 — At least one ring containing stereobonds

Overview

Open PHACTS and chemical validation and standardizationRDF for chemoinformatics calculationsGeneral case study: ChEMBLSugar case study: Perspective perception

Sugar depiction challenges

Stereochemistry not stored in V2000 format (though present in .cdx).

Consequences

ChEMBL(19275)

DrugBank(153)

Sugar questions

5359 27.8% 138 90.2% At least one L-pyranose ring (often antibiotics contain these)

4748 24.6% 0 — At least one perspective chair

416 2.16% 0 — At least one Haworth ring

52 0.03% 0 — At least one perspective boat or twist boat

Sugar ring redepiction algorithm

1. Identify perspective conformation (boat, chair, Haworth)

2. Determine perspective stereo3. Assign wedge or hash to bonds accordingly4. Reconstruct sugar ring so as to minimize

disruption to the rest of molecule5. Tidy

Take the x-axis as parallel to the line through the top two chair atoms or through the bottom two chair atoms.

Δy positive: wedgeΔy negative: hash

Then remap chair to homotropous hexagon.

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.

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).

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.

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.

Acknowledgements

In particular,Jon Steele (RSC)

David Sharpe (RSC)John Blunt (Canterbury, NZ)

Any questions?

[email protected]@documentvector

Education

20130724 cisrg sugars_batchelor