Delivering an online service for validating and standardizing chemical structure files using the ChemSpider platform

Overview Introduction – Why do we need to validate/standardise data – Examples of problems in general – Examples of Problems in ChemSpider – Why InChI is not enough – FDA rules

What are we trying to achieve? Everyone wants high quality data The ChemSpider team is building a reputation on data quality Many datasources have errors We need to identify: – Errors – Inconsistencies – Data duplication/Inappropriate separation of data Requires a process of validation and standardization

What do we mean by Validation and Standardisation? Validated – Check for hypervalency, charge balance, missing stereo – Name-Structure relationships, etc. Standardized – Use standard rules to “standardize” compounds; Nitro groups, O-Metal bonds, tautomers, etc.

Where will CVSP be useful Currently, a standalone system In the future; Validation/standardisation routines will be used: – Built in to our deposition system – At registration for new compounds – To improve existing data in ChemSpider – pass through the ChemSpider backfile Potential to offer optional checking service to authors

What we want to avoid

What do we do now? Currently, ChemSpider uses structures (as InChI’s) as the database key Need structures for depositions 2 Steps: – Pre-processing prior to deposition – InChI algorithm; provides standardisation and mapping

What are the common errors? Records without a structure Incorrect valences Atom labels

What are the common errors? Unbalanced charge – Name-structure errors Salts Polymers/Organometallics Missing stereochemistry

Side Effects of InChI on ChemSpider: Sort of helpful

Side Effects of InChI on ChemSpider Advantages and disadvantages – The depictions are meant to represent the same molecule – Not easy to pick out “bad” representations

Substance Registry System How do you decide your standardisation rules? Avoid standards in isolation m-UniqueIngredientIdentifierUNII/ucm pdf Note: This document is only a starting point

Salt and Ionic Bonds

Nitro groups

Ammonium salts

Validation rules In XML: Code generated dynamically from rule set. Indigo API used behind the scenes.

Standardization rules Corrections stored in database: SMIRKS-based corrections and also proximity- based metal–non-metal reconnection.

Case study: DrugBank DrugBank ( maintained by David WishartDavid Wishart Database contains 6711 structures Widely regarded as a well curated, high quality dataset DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Knox C, Law V, Jewison T, Liu P, Ly S, Frolkis A, Pon A, Banco K, Mak C, Neveu V, Djoumbou Y, Eisner R, Guo AC, Wishart DS., Nucleic Acids Res., 2011, 39, Jan, D

ChemSpider Standardization Entire ChemSpider database will be standardized using modified FDA rule set Original Molfiles will be standardized and all properties (predicted properties, SMILES, InChIs, Names) will all be regenerated Standardization procedures automatically applied to all future depositions

CVSP as a Flexible System There will be various rules sets – Rigid pre-defined rules: e.g. Meeting FDA specifications as written, Open PHACTS modified rules set, etc. – Flexible user-defined rules: users upload their rules in our custom format (XML) – The Open PHACTS rule set will be open to the community to reuse

Incorporating CVSP into data processing platforms: Knime The workflow includes: – SDF reader – Indigo nodes – calls for ChemSpider validation Web services

Incorporating CVSP into data processing platforms: Knime Warning is returned as a result of processing

Summary Will release back results of DrugBank Alpha version of CVSP available: Will be a resource for the Community Will improve ChemSpider Still a long way to go….

Thank you Twitter: ChemSpider