Standards for Digital Data Representation 1) The IUPAC/NIST Chemical Identifier 2) IUPAC Terminology NSF Workshop Constructing a Kinetics Database NIST, April 19-20, 2004

Bad News: –There are more problems than you thought Good News: –NIST/IUPAC are trying to solve them for you The News

Data Tags STM – Scientific, Technical, Medical ‘Publication’ thermokinetics spectroscopy synthesis Chemistry

Data Tags IUPAC/NIST Chemical Identity – INChI Interdisciplinary Terms – Gold & Green STM – Scientific, Technical, Medical ‘Publication’ Chemistry

A Digital ‘Name’ for A Chemical Entity convert chemical structure to digital ‘signature’ To allow computers to: –Organize chemical data –Disseminate data (queries) –Manage quality control

Current Representations are Inadequate Drawing – for humans only CAS registry number –Arbitrary value (hard to find and confirm) –CAS Indexer may not match Specialist –Expensive, imprecise, incomplete, no hierarchy Connection Table –One compound – Many representations –Embedded ambiguities ‘Canonical’ Connection Table –No open standard

Reactive Intermediates Ions, radicals, excited states –In principle, no problem Equilibrated species –Must specify variability precisely Weakly bound complexes –OK if orientation is omitted Transition states –Maybe not necessary in data compilation

ChemWeb, 3/2002

Nature, May 23, 2002

Requirements Different compounds have different identifiers –All distinguishing structural information is included INChI - 1 INChI - 2 = =

Requirements One compound has only one identifier –Include only necessary information Same INChI = ==

Two Problems Chemicals –Fast isomerization (esp, H-atoms) –Unconventional connectivity Chemists –Differing conventions Depends on discipline, education and convenience –Imprecision/uncertainty

3 Steps to INChI Chemistry –‘Normalize’ Input Structure Implement chemical rules Math –‘Canonicalize’ (label the atoms) Equivalent atoms get the same label Format –‘Serialize’ Labeled Structure Output as character string (‘name’)

Normalize Simplify Divide structure into ‘layers’ –Each layer ‘refines’ structure Ignore ‘Electron Density’ –Ignore bond type and electron location Stereochemistry –sp 2 and sp 3 only –Free rotation around single bonds

formula connectivity stereo isotope Chemical Substances “Layers”

4 Connectivity ‘Sublayers’ Disconnect H-atoms and metals –Create skeleton Reconnect Fixed H-atoms –Represent multiple species Reconnect mobile H-atoms –A single species Reconnect metals-non-metal bonds –Represent bonds to metals

Ignore Electron Density Not required for compound identification –Represent ‘excited states’ Simplify representations –Delocalization, aromaticity, zwitterions, coordination …

Münchnones Simplify - Ignore Electrons

Mobile H-atom (Tautomer) Sublayer H-migration between 1,3 heteroatoms

Nitrobenzene

MSG tautomeric

MSG fixed

Ferrocene

Auxiliary Output Confirmation –Label stereogenic atoms –Identify equivalent atoms Warnings/Errors –Unusual valences –Unrecognized input ‘Reversibility’ –Coordinates –Bond/Charge Location

Testing - OK

Beta Testing

50 ms – 2 GHz PC Performance: Most Challenging NCI-NIH Structure

INChI FAQs How can you represent chemistry without electrons? –Chemistry is not represented, just identity –Whole molecule properties may be added (state, phase,..). Do big molecules have big INChIs? –Yes, just like systematic names How to handle other tautomer types, substructures,..? –Other software Is INChI reversible? –Partly - contains only data needed for ‘naming’ –Auxiliary fields can carry structure depiction information Is INChI extensible? –New layers can add refinement

Started Oct. 2002

/ Miloslav Nic, Jiri Jirat, Czech Republic

Converted - XML

My Point of View A forest of data dictionaries is growing –Horizontally and vertically We need to consider forest management Some day all reusable data will be tagged