Simplified molecular input line entry specification
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|Type of format||chemical file format|
The simplified molecular input line entry specification or SMILES is a specification for unambiguously describing the structure of chemical molecules 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 developed by Arthur Weininger and David Weininger in the late 1980s. It has since been modified and extended by others, most notably by Daylight Chemical Information Systems Inc. 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 (WLN), ROSDAL and SLN (Tripos Inc).
In August 2006, the IUPAC introduced the InChI as a standard for formula representation. SMILES is generally considered to have the advantage of being slightly more human-readable than InChI; it also has a wide base of software support with extensive theoretical (e.g., graph theory) backing.
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 can be written for a molecule. For example, CCO, OCC and C(O)C all specify the structure of ethanol. Algorithms have been developed to ensure the same SMILES is generated for a molecule regardless of the order of atoms in the structure. This SMILES is unique for each structure, although dependent on the canonicalisation 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 and do not simply manipulate strings as is sometimes thought. Various algorithms for generating Canonical SMILES have been developed, including those by Daylight Chemical Information Systems, OpenEye Scientific Software, MEDIT and Chemical Computing Group. A common application of Canonical SMILES is indexing and ensuring uniqueness of molecules in a database.
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 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 isotopes are specified.
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.
Atoms are represented by the standard abbreviation of the chemical elements, in square brackets, such as [Au] for gold. Brackets can be omitted for the "organic subset" of B, C, N, O, P, S, F, Cl, Br, and I. All other elements must be enclosed in brackets. If the brackets are omitted, the proper number of implicit hydrogen atoms is assumed; for instance the SMILES for water is simply O.
An atom holding one or more electrical charge(s) is enclosed in brackets (whichever is), followed by the symbol H if it is bonded to one or more atoms of hydrogen (these ones are followed by their number so, except if there is one only : NH4 for ammonium), then by the sign '+' for an positive charge or by '-' for an negative charge. Number of charges is specified after the sign (except if there is one only) ; however, it's also possible write the sign as many as the ion hold of charges : instead of "Ti+4", you can also write "Ti++++" (Titanium IV, Ti4+). Thus, the hydroxide anion is represented by [OH-], the oxonium cation is [OH3+] and the cobalt III cation (Co3+) is either [Co+3] or [Co+++].
Bonds between aliphatic atoms are assumed to be single unless specified otherwise and are implied by adjacency in the SMILES. For example the SMILES for ethanol can be written as CCO. Ring closure labels are used to indicate connectivity between non-adjacent atoms in the SMILES, which for cyclohexane and dioxane can be written as C1CCCCC1 and O1CCOCC1 respectively. For a second ring, the label will be 2 (naphthalene : c1cccc2c1cccc2), and so on. After 9, the label must be preceded by a '%', in order to differentiate it from two different labels bonded to the same atom (~C12~ will mean the atom of carbon hold the ring closure labels 1 and 2, whereas ~C%12~ will indicate one label only, the 12). Double and triple bonds are represented by the symbols '=' and '#' respectively as illustrated by the SMILES O=C=O (carbon dioxide) and C#N (hydrogen cyanide).
Aromatic C, O, S and N atoms are shown in their lower case 'c', 'o', 's' and 'n' respectively. Benzene, pyridine and furan can be represented respectively by the SMILES c1ccccc1, n1ccccc1 and o1cccc1. Bonds between aromatic atoms are, by default, aromatic although these can be specified explicitly using the ':' symbol. Aromatic atoms can be singly bonded to each other and biphenyl can be represented by c1ccccc1-c2ccccc2. Aromatic nitrogen bonded to hydrogen, as found in pyrrole must be represented as [nH] and imidazole is written in SMILES notation as n1c[nH]cc1.
Branches are described with parentheses, as in CCC(=O)O for propionic acid and C(F)(F)F for fluoroform. 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.
Configuration around double bonds is specified using the characters "/" and "\". For example, F/C=C/F (see depiction) is one representation of trans-difluoroethene, in which the fluorine atoms are on opposite sides of the double bond, whereas F/C=C\F (see depiction) is one possible representation of cis-difluoroethene, in which the Fs are on the same side of the double bond, as shown in the figure.
Configuration at tetrahedral carbon is specified by @ or @@. L-Alanine, the more common enantiomer of the amino acid alanine can be written as N[C@@H](C)C(=O)O (see depiction). The @@ specifier indicates that, when viewed from nitrogen along the bond to the chiral center, the sequence of substituents hydrogen (H), methyl (C) and carboxylate (C(=O)O) appear clockwise. D-Alanine can be written as N[C@H](C)C(=O)O (see depiction). The order of the substituents in the SMILES string is very important and D-alanine can also be encoded as N[C@@H](C(=O)O)C (see depiction).
Isotopes are specified with a number equal to the integer isotopic mass preceding the atomic symbol. Benzene in which one atom is carbon-14 is written as [14c]1ccccc1 and deuterochloroform is [2H]C(Cl)(Cl)Cl.
Application on some molecules
|Methyl isocyanate (MIC)||CH3–N=C=O||CN=C=O|
|Copper(II) sulfate||Cu2+ SO42-||[Cu+2].[O-]S(=O)(=O)[O-]|
|Pyrethrin II (C21H28O3)||COC(=O)C(\C)=C\C1C(C)(C)[C@H]1C(=O)O[C@@H]2C(C)=C(C(=O)C2)CC=CC=C|
|Aflatoxin B1 (C17H12O6)||O1C=C[C@H]([C@H]1O2)c3c2cc(OC)c4c3OC(=O)C5=C4CCC(=O)5|
|Glucose (glucopyranose) (C6H12O6)||OC[C@@H](O1)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)1|
|Cuscutin alias Bergenin (a resin) (C14H16O9)||OC[C@@H](O1)[C@@H](O)[C@H](O)[C@@H]2[C@@H]1c3c(O)c(OC)c(O)cc3C(=O)O2|
|A pheromone of the californian scale insect||CC(=O)OCCC(/C)=C\C[C@H](C(C)=C)CCC=C|
|2S,5R-Chalcogran : a pheromone of the bark beetle Pityogenes chalcographus||CC[C@H](O1)CC[C@@]12CCCO2|
Illustration with a molecule with more of 9 rings, the Cephalostatin-1 (a steroidic trisdecacyclic pyrazine with the empirical formula C54H74N2O10 isolated from the Indian Ocean hemichordate Cephalodiscus gilchristi) :
Will give, starting by the most left methyle radical on the figure :
(Notice the '%' in front of the indice of the ring closure labels upper to 9, see the section "Bonds", higher).
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.
SMARTS is a line notation for specification of substructural patterns in molecules. While it uses many of the same symbols as SMILES, it also allows specification of wildcard atoms and bonds, which can be used to define substructural queries for chemical database searching. One common misconception is that SMARTS-based substructural searching involves matching of SMILES and SMARTS strings. In fact, both SMILES and SMARTS strings are first converted to internal graph representations which are searched for subgraph isomorphism. SMIRKS is a line notation for specifying reaction transforms.
SMILES can be converted back to 2-dimensional representations using Structure Diagram Generation algorithms (Helson, 1999). This conversion is not always unambiguous. Conversion to 3-dimensional representation is achieved by energy minimization approaches. There are many downloadable and web-based conversion utilities.
- Smiles arbitrary target specification SMARTS language for specification of substructural queries.
- SYBYL Line Notation (another line notation)
- Molecular Query Language - query language allowing also numerical properties, e.g. physicochemical values or distances
- Chemistry Development Kit (2D layout and conversion)
- International Chemical Identifier (InChI), the free and open alternative to SMILES by the IUPAC.
- OpenBabel, JOELib, OELib (conversion)
- Indigo (2D layout, conversion, canonicalization)
- Anderson, E.; Veith, G.D; Weininger, D. (1987) SMILES: A line notation and computerized interpreter for chemical structures. Report No. EPA/600/M-87/021. U.S. EPA, Environmental Research Laboratory-Duluth, Duluth, MN 55804
- Weininger, D. (1988), SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules, J. Chem. Inf. Comput. Sci. 28, 31-36.
- Weininger, D.; Weininger, A.; Weininger, J.L. (1989) SMILES. 2. Algorithm for generation of unique SMILES notation J. Chem. Inf. Comput. Sci. 29, 97-101.
- Helson, H.E. (1999) Structure Diagram Generation In Rev. Comput. Chem. edited by Lipkowitz, K. B. and Boyd, D. B. Wiley-VCH, New York, pages 313-398.
- "SMILES - A Simplified Chemical Language"
- The OpenSMILES home page
- "SMARTS - SMILES Extension"
- Daylight SMILES tutorial
- Parsing SMILES
SMILES related software utilities
- Online SMILES Translator and Structure File Generator – Java online molecule editor
- PubChem server side structure editor – online molecule editor
- smi23d – 3D Coordinate Generation
- Daylight Depict – Translate a SMILES formula into graphics
- GIF/PNG-Creator for 2D Plots of Chemical Structures
- JME molecule editor
- Marvin by ChemAxon – online chemical editor/viewer and SMILES generator/converter
- Instant JChem by ChemAxon – desktop application for storing/generating/converting/visualizing/searching SMILES structures, particularly batch processing; personal edition free
- JChem for Excel by ChemAxon – MS Excel add-in for storing/generating/converting/visualizing/searching SMILES structures
- Smormo-Ed – a molecule editor for Linux which can read and write SMILES
- InChI.info – an unofficial InChI website featuring on-line converter from InChI and SMILES to molecular drawings
- Balloon – A free program for 3D coordinate generation and conformational analysis.