3. Line Notations

        The Simplified Molecular-Input Line-Entry System (SMILES)^18-21 is a line notation for describing chemical structures using short ASCII strings.  SMILES was developed in the late 1980s and implemented by Daylight Chemical Information Systems (Santa Fe, NM), but it is still widely used today.  A detailed information on SMILES can be found in Chapter 3²⁶ of the Daylight Theory Manual as well as the SMILES tutorial²⁷.

• SMILES Specification Rules

        In SMILES, atoms are represented by their atomic symbols.  The second letter of two-character atomic symbols must be entered in lower case (e.g., Cl not CL; Br not BR).  Each non-hydrogen atom is specified independently by its atomic symbol enclosed in square brackets, [ ] (for example, [Au] or [Fe]).  Square brackets may be omitted for elements in the “organic subset” (B, C, N, O, P, S, F, Cl, Br, and I) if the proper number of “implicit” hydrogen atoms is assumed.  “Explicitly” attached hydrogens and formal charges are always specified inside brackets. A formal charge is represented by one of the symbols + or -.  Single, double, triple, and aromatic bonds are represented by the symbols, -, =, #, and :, respectively.  Single and aromatic bonds may be, and usually are, omitted.  Here are some examples of SMILES strings.

C               Methane (CH₄)

CC             Ethane (CH₃CH₃)

C=C           Ethene (CH₂CH₂)

C#C           Ethyne (CHCH)

COC           Dimethyl ether (CH3OCH3)

CCO           Ethanol (CH3CH2OH)

CC=O         Acetaldehyde (CH3-CH=O)

C#N           Hydrogen Cyanide (HCN)

[C-]#N       Cyanide anion

Branches are specified by enclosures in parentheses and can be nested or stacked, as shown in these examples.

CC(C)CO                         Isobutyl alcohol (CH₃-CH(CH₃)-CH₂-OH)

CC(CCC(=O)N)CN           5-amino-4-methylpentanamide

Rings are represented by breaking one single or aromatic bond in each ring, and designating this ring-closure point with a digit immediately following the atoms connected through the broken bond.  Atoms in aromatic rings are specified by lower cases letters.  Therefore, cyclohexane and benzene can be represented by the following SMILES.

C1CCCCC1        Cyclohexane (C₆H₁₂)

c1ccccc1           Benzene (C₆H₆)

Although the carbon-carbon bonds in these two SMILES are omitted, it is possible to deduce that the omitted bonds are single bonds (for cyclohexane) and aromatic bonds (for benzene).  One can also represent an aromatic compound as a non-aromatic, KeKulé structure. For example, the following is a valid SMILES string for benzene.

C1=CC=CC=C1         Benzene (C₆H₆)

Note that aromaticity is not a measurable physical quantity, but a concept without a unanimous mathematical definition.  As a result, different aromaticity detection algorithms often disagree with each other on whether a given molecule is aromatic or not, making it difficult to interchange information between databases that use different aromaticity detection algorithms for SMILES generation.

Also note that a ring structure can have multiple potential ring-closure points. For example, a six-membered ring has six bonds, each of which can be a ring-closure point.  As a result, a ring compound may be represented by many different but equally valid SMILES strings.  Actually, it is very common that there are a lot of SMILES strings that represent the same structure, whether it has a ring or not, because one can start with any atom in a molecule to derive a SMILES string.  Therefore, it is necessary to select a “unique SMILES” for a molecule among many possibilities.  Because this is done through a process called “canonicalization”, this unique SMILES string is also called the “canonical SMILES”.

• Isomeric SMILES

        Isomeric SMILES allows for specifying isotopism and stereochemistry of a molecule.  Information on isotopism is indicated by the integral atomic mass preceding the atomic symbol.  The atomic mass must be specified inside square brackets.  For example, C-13 methane can be represented by “[13CH4]”.  Configuration around double bonds is specified by “directional bonds” (characters / and \).  For example, E- and Z-1,2-difluoroethene can be represented by the following isomeric SMILES:

F/C=C/F or F\C=C\F         (E)-1,2-difluoroethene (trans isomer)

F/C=C\F or F\C=C/F         (Z)-1,2-difluoroethene (cis isomer)

Configuration around tetrahedral centers are indicated by the symbols “@” or “@@”

C[C@@H](C(=O)O)N        L-Alanine

C[C@H](C(=O)O)N           D-Alanine

More detailed information on chirality specification can be found in Chapter 3²⁶ of the Daylight Theory Manual.

• Limitations of SMILES

        SMILES is proprietary and it is not an open project.  This has led different chemical software developers to use different SMILES generation algorithms, resulting in different SMILES versions for the same compound.  Therefore, SMILES strings obtained from different databases or research groups are not interchangeable unless they used the same software to generate the SMILES strings.  With an aim to address this interchangeability issue of SMILES, an open-source project has launched to develop an open, standard version of the SMILES language called OpenSMILES.²⁸  However, the most noticeable community effort in this area is development of InChI, which is described in next section.

• InChI

        The IUPAC International Chemical Identifier (InChI)^22-25 was originally developed by the IUPAC and continuing development efforts have been made by the InChI Trust²⁵.  InChI is non-proprietary, open-source, and freely available to the scientific community.  Especially, because the software for generating InChI strings is also freely available, it avoids the interoperability issue that different implementations of SMILES language have.

        InChI encodes a chemical structure into “layers”.  Each layer holds a distinct and separable class of structural information, with the layers ordered to provide successive structural refinement.  There are currently six InChI layer types, each different class of structural information: the main layer, a charge layer, a stereochemical layer, an isotopic layer, a fixed-H layer and a reconnected layer.  The main layer, which specifies chemical formula, atoms, and bonds between them, is required for all InChIs.  However, the other layers appear only when corresponding input information is provided.  Layers and sublayers start with “/” (forward slash) followed by a letter denoting the identity of the layer (except for the chemical formula layer).  Below are some examples of InChI.

InChI=1S/CH4/h1H4 (methane)

InChI=1S/C2H6/c1-2/h1-2H3 (ethane)

InChI=1S/C2H6O/c1-2-3/h3H,2H2,1H3 (ethanol)

InChI=1S/C3H7NO2/c1-2(4)3(5)6/h2H,4H2,1H3,(H,5,6)/t2-/m0/s1 (L-alanine)

These InChI strings are not easy for a human to understand (especially compared to SMILES strings).  It is because InChI was developed as a “machine-readable” chemical identifier, with an aim to enable a computer to regenerate the corresponding chemical structure from the InChI string generated by another computer.  For this reason, InChI is often called as the bar code for chemical structures.

        Because the layered structure of InChI allows one to represent a chemical structure with a desired level of details, InChI software may generate different InChI strings for the same molecule.  This flexibility may be regarded as an obstacle to standardization and interoperability.  In response to this concern, the standard InChI was introduced which contains the same level of structural details and the same conventions for drawing perception, by using standard option settings in InChI software.  The standard InChI representations begin with “InChI=1S/”, while the non-standard InChI begins with “InChI=1/”.  The digit “1” following “InChI=” is the current InChI version number.

• InChIKey

        The length of an InChI string increases with the size of the corresponding chemical structure, and it is very common that molecules with more than 100 atoms result in very long InChI strings, which are not appropriate to use in internet search engines (such as Google, Yahoo, Bing, and so on).  In addition, these search engines do not care about case sensitivity nor special characters used in InChI.  To address this issue, the InChIKey was introduced for Internet and database searching/indexing.  It is a 27-character string derived from InChI, using a hashing algorithm.  Hashing is a one-way mathematical transformation typically used to calculate a compact fixed length digital representation of a much longer string of arbitrary length.

        The InChIKey consists of three blocks, separated by hyphens, for example:

BSYNRYMUTXBXSQ-UHFFFAOYSA-N (aspirin)

HEFNNWSXXWATRW-UHFFFAOYSA-N (ibuprofen)

RZVAJINKPMORJF-UHFFFAOYSA-N (acetaminophen)

The first block of 14 characters (out of 27 characters in total) encodes core molecular constitution, described by the InChI main layer.  The other structural features (such as stereochemistry, isotopic substitution, exact position of hydrogens, and metal ligation data) are encoded into the second block.  The protonation or deprotonation state is encoded in the last InChIKey character.

        Many databases such as PubChem²⁹, ChemSpider³⁰, ChEBI³¹, and NIST Chemistry Webbook ³² accept InChI and InChIKey strings as queries to search for chemical structures.  InChIs and InChIKeys can also be used as queries in UniChem³³ to produce cross-references between chemical structure identifiers from different databases.

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