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The simplified molecular-input line-entry system (SMILES) is a specification in the form of a
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.
The original SMILES specification was initiated by
It has since been modified and extended by others, most notably by
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 (such as graph theory).
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,
C(O)C 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 (e.g. cuneane, 1,2-dicyclopropylethane) 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.
In terms of a graph-based computational procedure, SMILES is a string obtained by printing the symbol nodes encountered in a
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 (incl. toxicity and
- 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 (typically their normal valence, but for N and P it is 3 or 5, and for S it is 2, 4 or 6), 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
[OH2]. Hydrogen may also be written as a separate atom; water may also be written as
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,
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-CO, but is usually written
Double, triple, and quadruple bonds are represented by the symbols
$ respectively as illustrated by the SMILES
O=C=O (carbon dioxide CO2),
C#N (hydrogen cyanide HCN) and
[Ga+]$[As-] (gallium arsenide).
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
[Na+].[Cl-] to show the dissociation.
An aromatic "one and a half" bond may be indicated with
:; see § Aromaticity below.
Single bonds adjacent to double bonds may be represented using
\ to indicate stereochemical configuration; see § Stereochemistry below.
Ring structures are written by breaking each ring at an arbitrary point (although some choices will lead to a more legible SMILES than others) to make an acyclic structure and adding numerical ring closure labels to show connectivity between non-adjacent atoms.
O1CCOCC1respectively. For a second ring, the label will be 2. For example, decalin
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
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
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=1CC=1. (The first form is preferred.)
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
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.
- In Kekulé form with alternating single and double bonds, e.g.
- Using the aromatic bond symbol
- Most commonly, by writing the constituent B, C, N, O, P and S atoms in lower-case forms
In the latter case, bonds between two aromatic atoms are assumed (if not explicitly shown) to be aromatic bonds. Thus, benzene, pyridine and furan can be represented respectively by the SMILES
When aromatic atoms are singly bonded to each other, such as in biphenyl, a single bond must be shown explicitly:
c1ccccc1-c2ccccc2. This is one of the few cases where the single bond symbol
- is required. (In fact, most SMILES software can correctly infer that the bond between the two rings cannot be aromatic and so will accept the nonstandard form
The Daylight and OpenEye algorithms for generating canonical SMILES differ in their treatment of aromaticity.
Branches are described with parentheses, as in
CCC(=O)O for propionic acid and
FC(F)F for fluoroform. The first atom within the parentheses, and the first atom after the parenthesized group, are both bonded to the same branch point atom. The bond symbol must appear inside the parentheses; outside (E.g.:
CCC=(O)O) is invalid.
Substituted rings can be written with the branching point in the ring as illustrated by the SMILES
COc(c1)cccc1C#N (see depiction) and
COc(cc1)ccc1C#N (see depiction) which encode the 3 and 4-cyanoanisole isomers. Writing SMILES for substituted rings in this way can make them more human-readable.
Branches may be written in any order. For example, bromochlorodifluoromethane may be written as
C(F)(Cl)(F)Br, or the like. Generally, a SMILES form is easiest to read if the simpler branch comes first, with the final, unparenthesized portion being the most complex. The only caveats to such rearrangements are:
- If ring numbers are reused, they are paired according to their order of appearance in the SMILES string. Some adjustments may be required to preserve the correct pairing.
- If stereochemistry is specified, adjustments must be made; see Stereochemistry § Notes below.
The one form of branch which does not require parentheses are ring-closing bonds. Choosing ring-closing bonds appropriately can reduce the number of parentheses required. For example, toluene is normally written as
c1ccccc1C, avoiding the parentheses required if written as
SMILES permits, but does not require, specification of
Configuration around double bonds is specified using the characters
\ to show directional single bonds adjacent to a double bond. For example,
F/C=C/F (see depiction) is one representation of
Bond direction symbols always come in groups of at least two, of which the first is arbitrary. That is,
F\C=C\F is the same as
F/C=C/F. When alternating single-double bonds are present, the groups are larger than two, with the middle directional symbols being adjacent to two double bonds. For example, the common form of (2,4)-hexadiene is written
As a more complex example,
Configuration at tetrahedral carbon is specified by
@@. Consider the four bonds in the order in which they appear, left to right, in the SMILES form. Looking toward the central carbon from the perspective of the first bond, the other three are either clockwise or counter-clockwise. These cases are indicated with
@, respectively (because the
@ symbol itself is a counter-clockwise spiral).
For example, consider the
N[[email protected]@H](C)C(=O)O(see depiction). Looking from the nitrogen–carbon bond, the hydrogen (
H), methyl (
C), and carboxylate (
C(=O)O) groups appear clockwise. D-Alanine can be written as
N[[email protected]](C)C(=O)O(see depiction
While the order in which branches are specified in SMILES is normally unimportant, in this case it matters; swapping any two groups requires reversing the chirality indicator. If the branches are reversed so alanine is written as
NC(C(=O)O)C, then the configuration also reverses; L-alanine is written as
N[[email protected]](C(=O)O)C (see depiction). Other ways of writing it include
OC(=O)[[email protected]@H](N)C and
Normally, the first of the four bonds appears to the left of the carbon atom, but if the SMILES is written beginning with the chiral carbon, such as
C(C)(N)C(=O)O, then all four are to the right, but the first to appear (the
[CH] bond in this case) is used as the reference to order the following three: L-alanine may also be written
The SMILES specification includes elaborations on the
@ symbol to indicate stereochemistry around more complex chiral centers, such as trigonal bipyramidal molecular geometry.
|Methyl isocyanate (MIC)||CH3−N=C=O|
|Pyrethrin II (C22H28O5)|
|Aflatoxin B1 (C17H12O6)|
|Glucose (β-D-glucopyranose) (C6H12O6)|
|Bergenin (cuscutin, a resin) (C14H16O9)|
|A pheromone of the Californian scale insect|
|Thiamine (vitamin B1, C12H17N4OS+)|
To illustrate a molecule with more than 9 rings, consider cephalostatin-1, a steroidic 13-ringed pyrazine with the empirical formula C54H74N2O10 isolated from the Indian Ocean hemichordate Cephalodiscus gilchristi:
Starting with the left-most methyl group in the figure:
CC(C)(O1)C[[email protected]@H](O)[[email protected]@]1(O2)[[email protected]@H](C)[[email protected]@H]3CC=C4[[email protected]]3(C2)C(=O)C[[email protected]]5[[email protected]]4CC[[email protected]@H](C6)[[email protected]]5(C)Cc(n7)c6nc(C[[email protected]@]89(C))c7C[[email protected]@H]8CC[[email protected]@H]%10[[email protected]@H]9C[[email protected]@H](O)[[email protected]@]%11(C)C%10=C[[email protected]](O%12)[[email protected]]%11(O)[[email protected]](C)[[email protected]]%12(O%13)[[email protected]](O)C[[email protected]@]%13(C)CO
% appears in front of the index of ring closure labels above 9; see § Rings above.
Other examples of SMILES
The SMILES notation is described extensively in the SMILES theory manual provided by Daylight Chemical Information Systems and a number of illustrative examples are presented. Daylight's depict utility provides users with the means to check their own examples of SMILES and is a valuable educational tool.
SMIRKS, a superset of "reaction SMILES" and a subset of "reaction SMARTS", is a line notation for specifying reaction transforms. The general syntax for the reaction extensions is
REACTANT>AGENT>PRODUCT (without spaces), where any of the fields can either be left blank or filled with multiple molecules deliminated with a dot (
.), and other descriptions dependent on the base language. Atoms can additionally be identified with a number (e.g.
[C:1]) for mapping, for example in .
SMILES corresponds to discrete molecular structures. However many materials are macromolecules, which are too large (and often stochastic) to conveniently generate SMILES for. BigSMILES is an extension of SMILES that aims to provide an efficient representation system for macromolecules.
SMILES can be converted back to two-dimensional representations using structure diagram generation (SDG) algorithms. This conversion is not always unambiguous. Conversion to three-dimensional representation is achieved by energy-minimization approaches. There are many downloadable and web-based conversion utilities.
- SMILES arbitrary target specification(SMARTS), an extension of SMILES for specification of substructural queries
- SYBYL Line Notation, another line notation
- IUPAC's alternative to SMILES
- Molecular Query Language, a query language allowing also numerical properties, e.g. physicochemical values or distances
- Chemistry Development Kit, 2D layout and conversion software
- Weininger D (1998). "Acknowledgements on Daylight Tutorial smiles-etc page". Retrieved June 24, 2013.
- Anderson E, Veith GD, Weininger D (1987). SMILES: A line notation and computerized interpreter for chemical structures (PDF). Duluth, MN: U.S. EPA, Environmental Research Laboratory-Duluth. Report No. EPA/600/M-87/021.
- "SMILES Tutorial: What is SMILES?". U.S. EPA. Archived from the original on March 28, 2008. Retrieved September 23, 2012.
- "CID 183413". PubChem. Retrieved May 12, 2012.
- "SMIRKS Tutorial". Daylight Chemical Information Systems, Inc. Retrieved October 29, 2018.
- "Reaction SMILES and SMIRKS". Daylight Chemical Information Systems, Inc. Retrieved October 29, 2018.