Simplified Molecular Input Line Entry System

The Simplified Molecular Input Line Entry System is a specification in the form of a line notation for describing the structure of chemical species using short ASCII strings. SMILES strings can be imported by most molecule editors for conversion back into two-dimensional drawings or three-dimensional models of the molecules.
The original SMILES specification was initiated in the 1980s. It has since been modified and extended. In 2007, an open standard called OpenSMILES was developed in the open source chemistry community.

History

The original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. Acknowledged for their parts in the early development were "Gilman Veith and Rose Russo and Albert Leo and Corwin Hansch for supporting the work, and Arthur Weininger and Jeremy Scofield for assistance in programming the system." The Environmental Protection Agency funded the initial project to develop SMILES.
It has since been modified and extended by others, most notably by Daylight Chemical Information Systems. In 2007, an open standard called "OpenSMILES" was developed by the Blue Obelisk open-source chemistry community. Other 'linear' notations include the Wiswesser Line Notation, ROSDAL and SLN.
In July 2006, the IUPAC introduced the InChI as a standard for formula representation. SMILES is generally considered to have the advantage of being more human-readable than InChI; it also has a wide base of software support with extensive theoretical backing.

Terminology

The term SMILES refers to a line notation for encoding molecular structures and specific instances should strictly be called SMILES strings. However, the term SMILES is also commonly used to refer to both a single SMILES string and a number of SMILES strings; the exact meaning is usually apparent from the context. The terms "canonical" and "isomeric" can lead to some confusion when applied to SMILES. The terms describe different attributes of SMILES strings and are not mutually exclusive.
Typically, a number of equally valid SMILES strings can be written for a molecule. For example, CCO, OCC and CC all specify the structure of ethanol. Algorithms have been developed to generate the same SMILES string for a given molecule; of the many possible strings, these algorithms choose only one of them. This SMILES is unique for each structure, although dependent on the canonicalization algorithm used to generate it, and is termed the canonical SMILES. These algorithms first convert the SMILES to an internal representation of the molecular structure; an algorithm then examines that structure and produces a unique SMILES string. Various algorithms for generating canonical SMILES have been developed and include those by Daylight Chemical Information Systems, OpenEye Scientific Software, MEDIT, Chemical Computing Group, MolSoft LLC, and the Chemistry Development Kit. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database.
The original paper that described the CANGEN algorithm claimed to generate unique SMILES strings for graphs representing molecules, but the algorithm fails for a number of simple cases and cannot be considered a correct method for representing a graph canonically. There is currently no systematic comparison across commercial software to test if such flaws exist in those packages.
SMILES notation allows the specification of configuration at tetrahedral centers, and double bond geometry. These are structural features that cannot be specified by connectivity alone, and therefore SMILES which encode this information are termed isomeric SMILES. A notable feature of these rules is that they allow rigorous partial specification of chirality. The term isomeric SMILES is also applied to SMILES in which isomers are specified.

Graph-based definition

In terms of a graph-based computational procedure, SMILES is a string obtained by printing the symbol nodes encountered in a depth-first tree traversal of a chemical graph. The chemical graph is first trimmed to remove hydrogen atoms and cycles are broken to turn it into a spanning tree. Where cycles have been broken, numeric suffix labels are included to indicate the connected nodes. Parentheses are used to indicate points of branching on the tree.
The resultant SMILES form depends on the choices:

of the bonds chosen to break cycles,
of the starting atom used for the depth-first traversal, and
of the order in which branches are listed when encountered.
SMILES definition as strings of a context-free language

From the view point of a formal language theory, SMILES is a word. A SMILES is parsable with a context-free parser. The use of this representation has been in the prediction of biochemical properties based on the main principle of chemoinformatics that similar molecules have similar properties. The predictive models implemented a syntactic pattern recognition approach as well as a more robust scheme based on statistical pattern recognition.

Description

Atoms

s are represented by the standard abbreviation of the chemical elements, in square brackets, such as for gold. Brackets may be omitted in the common case of atoms which:

are in the "organic subset" of B, C, N, O, P, S, F, Cl, Br, or I, and
have no formal charge, and
have the number of hydrogens attached implied by the SMILES valence model, and
are the normal isotopes, and
are not chiral centers.

All other elements must be enclosed in brackets, and have charges and hydrogens shown explicitly. For instance, the SMILES for water may be written as either O or . Hydrogen may also be written as a separate atom; water may also be written as O.
When brackets are used, the symbol H is added if the atom in brackets is bonded to one or more hydrogen, followed by the number of hydrogen atoms if greater than 1, then by the sign + for a positive charge or by - for a negative charge. For example, for ammonium. If there is more than one charge, it is normally written as digit; however, it is also possible to repeat the sign as many times as the ion has charges: one may write either or for titanium Ti⁴⁺. Thus, the hydroxide anion is represented by , the hydronium cation is and the cobalt cation is either or .

Bonds

A bond is represented using one of the symbols . - = # $ : / \.
Bonds between aliphatic atoms are assumed to be single unless specified otherwise and are implied by adjacency in the SMILES string. Although single bonds may be written as -, this is usually omitted. For example, the SMILES for ethanol may be written as C-C-O, CC-O or C-CO, but is usually written CCO.
Double, triple, and quadruple bonds are represented by the symbols =, #, and $ respectively as illustrated by the SMILES O=C=O, C#N and $.
An additional type of bond is a "non-bond", indicated with ., to indicate that two parts are not bonded together. For example, aqueous sodium chloride may be written as . to show the dissociation.
An aromatic "one and a half" bond may be indicated with :; see below.
Single bonds adjacent to double bonds may be represented using / or \ to indicate stereochemical configuration; see below.

Rings

Ring structures are written by breaking each ring at an arbitrary point to make an acyclic structure and adding numerical ring closure labels to show connectivity between non-adjacent atoms.
For example, cyclohexane and dioxane may be written as C1CCCCC1 and O1CCOCC1 respectively. For a second ring, the label will be 2. For example, decalin may be written as C1CCCC2C1CCCC2.
SMILES does not require that ring numbers be used in any particular order, and permits ring number zero, although this is rarely used. Also, it is permitted to reuse ring numbers after the first ring has closed, although this usually makes formulae harder to read. For example, bicyclohexyl is usually written as C1CCCCC1C2CCCCC2, but it may also be written as C0CCCCC0C0CCCCC0.
Multiple digits after a single atom indicate multiple ring-closing bonds. For example, an alternative SMILES notation for decalin is C1CCCC2CCCCC12, where the final carbon participates in both ring-closing bonds 1 and 2. If two-digit ring numbers are required, the label is preceded by %, so C%12 is a single ring-closing bond of ring 12.
Either or both of the digits may be preceded by a bond type to indicate the type of the ring-closing bond. For example, cyclopropene is usually written C1=CC1, but if the double bond is chosen as the ring-closing bond, it may be written as C=1CC1, C1CC=1, or C=1CC=1. C=1CC-1 is illegal, as it explicitly specifies conflicting types for the ring-closing bond.
Ring-closing bonds may not be used to denote multiple bonds. For example, C1C1 is not a valid alternative to C=C for ethylene. However, they may be used with non-bonds; C1.C2.C12 is a peculiar but legal alternative way to write propane, more commonly written CCC.
Choosing a ring-break point adjacent to attached groups can lead to a simpler SMILES form by avoiding branches. For example, cyclohexane-1,2-diol is most simply written as OC1CCCCC1O; choosing a different ring-break location produces a branched structure that requires parentheses to write.