Notes

Outline

InChI The IUPAC International Chemical Identifier

InChI: NIST Parentage NIST/EPA/NIH Mass Spectral Database (1976) 32,000 connection tables for DOS display (1986) Structures & Properties (1990) Reference Data & Structure-Based Property Prediction NIST Chemistry Webbook (1991) Proposed ‘Standard’ canonical connection table (1992) Too early NIST + IUPAC (2000)

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2002-2005 Salts and H-migration Organometallics Protonation Test/refinement Final InChI structure

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Formal Requirement 1 Different compounds have different identifiers All distinguishing structural information is included

Formal Requirement 2 A compound has a single identifier Include only necessary information

Practical Requirements Represent common ‘equilibrated mixtures’ Handles incomplete stereochemistry Deal with coordination/imprecise bonding Suitable for individual and community

Two Problems Chemicals Equilibrated Mixtures Tautomerization, protonation Imprecise connectivity Organometallics, boranes Chemists Differing conventions Depends on discipline, education and convenience Unrecognized uncertainty ‘Don’t know what they don’t know’ Graphics oriented

Chemical or Mixture? A ‘Chemical’ is often an equilibrium mixture of set of distinct entities H2SO4 ó H+ + HSO4– ó 2H + + SO4–2 RCO2H ó H+ + RCO2 – Depends on chemical environment (pH, T, …) Details often not known

Must Deal with Common Input Ambiguities

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’)

Normalization Divide input structure into ‘layers’ Each layer ‘refines’ structure Ignore ‘Electron Density’ Use simple ‘connectivity’ only Ignore bond type and charge location Stereochemistry sp2 and sp3 only Free rotation around single bonds

Mostly Ignore Electron Density Not required for compound identification Difference densities => Different electronic states Simplification Delocalization, aromaticity, zwitterions, coordination … Use input bonding for stereo/tautomer perception When not otherwise specified

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IUPAC International Chemical Identifier (InChI) – Technical Issues

InChI Scope Discrete, covalently bonded compounds Isotopes Stereochemistry: sp3 (tetrahedral) sp2 (double bonds) Tautomers Variable Protonation

InChI Requirements: Unique Identifier One Compound « One Identifier: Compound = Chemical structure Identifier (InChI) = String of characters Produce same InChI from various representations of the same compound Possibility to restore a chemical structure from InChI

InChI Requirements: Layers to express the degree of details Empirical formula Molecular skeleton Structure with mobile hydrogen atoms Charge and proton balance Structure with fixed mobile hydrogen atom locations Isotopic composition Stereochemistry for: Mobile H Fixed Mobile H Mobile H, Isotopic Fixed Mobile H, Isotopic

Layered Identifier

Layered Identifier

Structure ® InChI: Normalization-1 Discover redundant information Reduce structure to common drawing conventions Remove/add protons to make charge closer to zero Discover possible locations of mobile charges Discover possible positions of mobile H Allow H, charges, and radicals to migrate to reduce the number of stereogenic elements

Structure ® InChI: Normalization-2 Discard: Electron density Bond order Charge/radical locations Aromaticity Excited states Stereo information for changeable bonds bonds in less than 8-member rings Keep: All atoms ± protons Connections between atoms Hydrogen atoms: All Mobile H locations Original  H locations Spatial arrangements around stereogenic bonds and atoms

Normalization Details-1 Reduction to common conventions

Normalization Details-2 Replacing charges with increased bond order

Normalization Details-3 Replacing charges with increased bond order

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Fixing bonds to preserve functional groups - Example

Rules for fixing bonds

Rules for fixing bonds (cont.)

Cancel radicals

Remove charges by adding and/or removing protons

Aggressive (De)protonation

Tautomerism definitions

Testing bonds

Testing Mobile H – similar to testing bonds

Canonicalization Obtaining canonical numbers of the atoms in the structure (based on a well-known graph algorithm by B. D. McKay, 1981 [6]) The numbers must be created in such a way that allows the layered structure of InChI: Adding each next layer does not change the preceding layers The identifier is unique

Simple Canonicalization Example

Canonicalization: the 1st colors

Canonicalization: equitable partition

Canonicalization: equitable partition Continue by using new “colors” as 1st colors and calculate next new colors until there are no more changes If there are still equal “colors” then reduce one of the smallest equal “colors” to the first color less than it + 1 and use this set of colors as 1st colors, etc., until all colors are different. Save the colors and the connection table. Repeat reductions of equal colors until all sequences of color reductions have been explored Keep the set of colors that provides the “smallest” connection table. These colors are canonical numbers.

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Canonicalization: find minimal connection table (shown 2 out of 16 possible numberings)

Canonicalization: find equivalent atoms and start over

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Canonicalization: other layers So far only the connections have been canonicalized. Each next layer requires adding one more ordered by canonical numbers list and a structural feature: Atoms H in fixed positions Groups of mobile H and attachment points Isotopic “weights” of atoms The minimization is repeated; it leaves unchanged all previously minimized preceding layers and adds one more

Canonicalization: Stereochemistry One more list containing triplets: ordered canonical numbers of atoms at the ends of stereogenic bonds and bond parity. One more list containing ordered canonical numbers of stereogenic atoms and their parities. Included is a heuristic algorithm that allows to recognize most of atoms and double bonds that are not stereogenic due to symmetry.

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2-D Drawing correctness  definitions (4 ligands)

2-D Drawing correctness  definitions (3 ligands)

Stereochemistry Representation

InChI creation options The options are designed to provide the InChI algorithm with information necessary to include known information and omit the unknown or unessential If a substance behaves as a mixture of tautomeric forms then do not include Fixed-H layer If stereochemistry is unknown but 3-D coordinates are provided then do not include the stereochemical layer If a maximum level of detail is needed to be included then include Fixed-H, Stereo, and Reconnected layers Make sure that 2D stereo drawing conventions are consistent with use of NEWPS option (see the next slide) If Absolute stereo is marked with the Chiral Flag then include the SUCF option If all hydrogen atoms are included in the structure then use DoNotAddH option

InChI creation options

InChI Stream Editor (SED) scripts InChI package includes a set of scripts designed to remove InChI layers to facilitate search and compare.

InChI Stream Editor (SED) scripts Replace Absolute stereo with Relative Remove Fixed-H layer from InChI Remove Isotopic layer from InChI Remove Stereochemical layer from InChI Remove "Include bonds to metal" layer from InChI Remove sp3 Stereo layer from InChI Remove Charge and Proton layers from InChI Remove Disconnected structure info from InChI Remove All Reversibility Info from AuxInfo Remove Exact Reversibility Info from AuxInfo Remove Mapping of canonical numbers from AuxInfo

wInChI Program

wInChI Annotated Output

wInChI Annotated Output  (continued)

wInChI Program Options

InChI validation protocol Designed primarily to verify that InChI code used in 3rd party applications works correctly InChI code ported to another compiler or operating system works correctly Contains Structures that test most of InChI logics described in InChI documentation InChI produced out of these structures Validation instructions (in preparation)

References S. Stein, S. Heller, D. Tchekhovskoi, "The IUPAC Chemical Identifier – Technical Manual", April 2005; http:/www.iupac.org/inchi. "User’s Guide: IUPAC International Chemical Identifier (InChI) Program", April 2005; http:/www.iupac.org/inchi. Mockus, J., Stobaugh, R. E,"The Chemical Abstracts Service Chemical Registry System. VII. Tautomerism and Alternating Bonds"; J. Chem. Inf. Comput. Sci. 1980, 20, pp. 18-22. Blackwood, J. E., Blower, P. E., Jr., Layten, S. W., Lillie, D. H., Lipkus, A. H., Peer, J. P., Qian, C., Staggenborg, L. M., Watson, C. E., "Chemical Abstracts Service Chemical Registry System. 13. Enhanced Handling of Stereochemistry", J. Chem. Inf. Comput. Sci., 1991, vol. 31, pp. 204-212. W. Kocay, D. Stone, "An Algorithm for Balanced Flows", The Journal of Combinatorial Mathematics and Combinatorial Computing, 1995, vol. 19, pp. 3-31. B. D. McKay, "Practical Graph Isomorphism", Congressus Numerantium, 1981, Vol. 30, pp. 45 – 87. G. Butler, “Fundamental Algorithms for Permutational Groups”, Berlin ; New York: Springer-Verlag, 1991 (Series: Lecture Notes in Computer Science, 559), Chapter 11.

INChI availability Standalone programs for Win32 and i386 Linux, including command line program InChI Software library: for linking to user’s application through InChI API Documentation, examples, SED scripts Source code Available for download at http://www.iupac.org/inchi

Current Applications NIH/NCBI – PubChem NIH/NCI Database EPA/DSSTox NIST Webbook ACD/ChemDraw EBI/ChEBI (coming) Others ….

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CML & InChI CML: a vehicle for chemical data transmission InChI:  a tag for chemical identification <molecule><identifier> <inchi>1/C14H22O2/c1-13(2,3)9-7-12(16)10(8-11(9)15)14(4,5)6/h1-6H3,7-8H,15-16H</inchi> <identifier></molecule>

Remaining Problem: No Accepted Depiction ‘Standards’ Hashed wedge Explicit H-representation Relative stereo and d/l mixtures Coordination compounds Tautomerism, protonation ….

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http://www.iupac.org/inchi

Nick Day’s InChI FAQ

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Take Home InChI represents isolated or H-equilibrated compounds. Care needed when preparing InChI input Legacy - switches or preprocessing New – appropriate user controls Layers allow structure detail, but add complexity Matching compounds may require layer processing Chemical Complexities Stereochemistry, tautomerism/protonation, other equilibration, bonds to metals, mixtures