Simplified Molecular Input Line Entry System: Difference between revisions

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{{Use mdy dates|date=July 2020}}

{{Infobox file format

| name = SMILES

| extension = .smi

| owner =

| mime = chemical/x-daylight-smiles

| genre = [[chemical file format]]

| owner =

| creatorcode =

| genre = [[chemical file format]]

| container for =

| contained by =

| extended from =

| extended to =

}}

[[Image:SMILES.png|thumb|class=skin-invert-image|300px|SMILES generation algorithm for [[ciprofloxacin]]: break cycles, then write as branches off a main backbone]]

The '''simplifiedSimplified molecular-inputMolecular line-entryInput systemLine Entry System''' ('''SMILES''') is a specification in the form of a [[line notation]] for describing the structure of [[chemical species]] using short [[ASCII]] [[string (computer science)|strings]]. SMILES strings can be imported by most [[molecule editor]]s for conversion back into [[two-dimensional]] drawings or [[dimension|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, Minnesota|Duluth]] in the 1980s.<ref name="Weininger-1988">{{cite journal| vauthors = Weininger D | title=SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules| journal=Journal of Chemical Information and Computer Sciences| volume=28| issue= 1|pages=31–6|date=February 1988|doi=10.1021/ci00057a005 }}</ref><ref name="Weininger-1989">{{cite journal| vauthors = Weininger D, Weininger A, Weininger JL | title=SMILES. 2. Algorithm for generation of unique SMILES notation| journal=Journal of Chemical Information and Modeling| volume=29| issue=2| pages=97–101|date=May 1989|doi=10.1021/ci00062a008 }}</ref><ref name="Weininger-1990">{{cite journal| vauthors = Weininger D | title=SMILES. 3. DEPICT. Graphical depiction of chemical structures| journal=Journal of Chemical Information and Modeling| volume=30| issue= 3|pages=237–43|date=August 1990|doi=10.1021/ci00067a005 }}</ref><ref name="Swanson-2004">{{cite book | vauthors = Swanson RP | veditors = Rayward WB, Bowden ME |title=The History and Heritage of Scientific and Technological Information Systems: Proceedings of the 2002 Conference of the American Society of Information Science and Technology and the Chemical Heritage Foundation |date=2004 |publisher=[[Information Today]] |___location=Medford, NJ |isbn=978-1-57387-229-4 |page=205 |url=https://books.google.com/books?id=76OOQannpBgC&pg=PA205 |ref=ASIST monograph series 2002 |chapter=The Entrance of Informatics into Combinatorial Chemistry |chapter-url=https://wayback.archive-it.org/2118/20100925010036/http://64.251.202.97/pubs/asist2002/17-swanson.pdf }}</ref> Acknowledged for their parts in the early development were "Gilman Veith and Rose Russo (USEPA) and Albert Leo and [[Corwin Hansch]] ([[Pomona College]]) for supporting the work, and Arthur Weininger (Pomona; Daylight CIS) and Jeremy Scofield (Cedar River Software, Renton, WA) for assistance in programming the system."<ref name="Weininger-1998">{{cite web| vauthors = Weininger D |title=Acknowledgements on Daylight Tutorial smiles-etc page|url=http://www.daylight.com/meetings/summerschool98/course/dave/smiles-etc.html|access-date=24 June 2013 |date=1998 }}</ref> The [[United States Environmental Protection Agency|Environmental Protection Agency]] funded the initial project to develop SMILES.<ref name="Anderson-1987">{{cite book |year=1987 |title= SMILES: A line notation and computerized interpreter for chemical structures |id=Report No. EPA/600/M-87/021 |publisher=[[United States Environmental Protection Agency|U.S. EPA]], Environmental Research Laboratory-Duluth |___location=Duluth, MN |url=https://nepis.epa.gov/Exe/ZyPDF.cgi/2000CAUR.PDF?Dockey=2000CAUR.PDF | vauthors = Anderson E, Veith GD, Weininger D }}</ref><ref name="SMILES Tutorial: What is SMILES?">{{Cite web|url=http://www.epa.gov/med/Prods_Pubs/smiles.htm | archive-url = https://web.archive.org/web/20080328080430/https://www.epa.gov/med/Prods_Pubs/smiles.htm | archive-date = 28 March 2008 |title=SMILES Tutorial: What is SMILES? |publisher=[[United States Environmental Protection Agency|U.S. EPA]] |access-date=2012-09-23 }}</ref>

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]] (WLN), [[ROSDAL]] and [[SYBYL Line Notation|SLN]] (Tripos Inc).

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==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 [[biodegradability]]) based on the main principle of chemoinformatics that similar molecules have similar properties. The predictive models implemented a syntactic pattern recognition approach (which involved defining a molecular distance)<ref>{{cite journal | vauthors = Sidorova J, Anisimova M | title = NLP-inspired structural pattern recognition in chemical application. | journal = Pattern Recognition Letters. | date = August 2014 | volume = 45 | pages = 11–16 | doi = 10.1016/j.patrec.2014.02.012 | bibcode = 2014PaReL..45...11S }}</ref> as well as a more robust scheme based on statistical pattern recognition.<ref>{{cite journal | vauthors = Sidorova J, Garcia J | title = Bridging from syntactic to statistical methods: Classification with automatically segmented features from sequences. | journal = Pattern Recognition | date = November 2015 | volume = 48 | issue = 11 | pages = 3749–3756 | doi = 10.1016/j.patcog.2015.05.001 | bibcode = 2015PatRe..48.3749S | hdl = 10016/33552 | hdl-access = free }}</ref>

== Description ==

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=== Atoms ===

[[Atom]]s are represented by the standard abbreviation of the [[chemical element]]s, in square brackets, such as <code>[Au]</code> for [[gold]]. Brackets may be omitted in the common case of atoms which:

# are in the "[[CHON|organic subset]]" of [[boron|B]], [[carbon|C]], [[nitrogen|N]], [[oxygen|O]], [[phosphorus|P]], [[sulfur|S]], [[fluorine|F]], [[chlorine|Cl]], [[bromine|Br]], or [[iodine|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 [[isotope]]s, and

# are not [[Stereocenter|chiral centers]].

All other elements must be enclosed in brackets, and have charges and hydrogens shown explicitly. For instance, the SMILES for [[water (molecule)|water]] may be written as either <code>O</code> or <code>[OH2]</code>. Hydrogen may also be written as a separate atom; water may also be written as <code>[H]O[H]</code>.

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An additional type of bond is a "non-bond", indicated with <code>.</code>, to indicate that two parts are not bonded together. For example, aqueous [[sodium chloride]] may be written as <code>[Na+].[Cl-]</code> to show the dissociation.

An aromatic "one and a half" bond may be indicated with <code>:</code>; see {{slinksection link||Aromaticity}} below.

Single bonds adjacent to double bonds may be represented using <code>/</code> or <code>\</code> to indicate stereochemical configuration; see {{slinksection link||Stereochemistry}} below.

===Rings===

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[[Aromaticity|Aromatic]] rings such as [[benzene]] may be written in one of three forms:

# In [[August Kekulé|Kekulé]] form with alternating single and double bonds, e.g. <code>C1=CC=CC=C1</code>,

# Using the aromatic bond symbol <code>:</code>, e.g. <code>C1C:1:C:C:C:C:C1</code>,{{Citation needed|date=June 2025|reason=Not mentioned in www.daylight.com/dayhtml/doc/theory/theory.smiles.html, probably SMARTS related.}} or

# Most commonly, by writing the constituent B, C, N, O, P and S atoms in lower-case forms <code>b</code>, <code>c</code>, <code>n</code>, <code>o</code>, <code>p</code> and <code>s</code>, respectively.

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The Daylight and OpenEye algorithms for generating canonical SMILES differ in their treatment of aromaticity.

[[Image:3-cyanoanisole SMILES.svg|right|thumb|class=skin-invert-image|350px|Visualization of 3-cyanoanisole as <code>COc(c1)cccc1C#N</code>.]]

=== Branching ===

Branches are described with parentheses, as in <code>CCC(=O)O</code> for [[propionic acid]] and <code>FC(F)F</code> 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 (Ee.g.: <code>CCC=(O)O</code>) is invalid.

Substituted rings can be written with the branching point in the ring as illustrated by the SMILES <code>COc(c1)cccc1C#N</code> ([https://web.archive.org/web/20130522091354/http://www.daylight.com/daycgi/depict?434f6328633129636363633143234e see depiction]) and <code>COc(cc1)ccc1C#N</code> ([https://web.archive.org/web/20130522074308/http://www.daylight.com/daycgi/depict?434f6328636331296363633143234e see depiction]) which encode the 3 and 4-cyanoanisole isomers. Writing SMILES for substituted rings in this way can make them more human-readable.

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Branches may be written in any order. For example, [[bromochlorodifluoromethane]] may be written as <code>FC(Br)(Cl)F</code>, <code>BrC(F)(F)Cl</code>, <code>C(F)(Cl)(F)Br</code>, 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 {{slinksection link||Stereochemistry}} below.

The one form of branch which does ''not'' require parentheses are ring-closing bonds: the SMILES fragment <code>C1N</code> is equivalent to <code>C(1)N</code>, both denoting a bond between the <code>C</code> and the <code>N</code>. Choosing ring-closing bonds appropriatelyadjacent to branch points can reduce the number of parentheses required. For example, [[toluene]] is normally written as <code>Cc1ccccc1</code> or <code>c1ccccc1C</code>, avoiding the parentheses required if written as <code>c1cc(C)ccc1</code> or <code>c1cc(ccc1)C</code>.

=== Stereochemistry ===

{{See also|Skeletal formula}}[[File:Trans-1,2-difluoroethylene.svg|thumb|right|class=skin-invert-image|upright=0.5|''trans''-1,2-difluoroethylene]]

<!--[[File:Cis-1,2-difluoroethylene.svg|thumb|right|class=skin-invert-image|upright=0.5|''cis''-1,2-difluoroethylene]]-->

SMILES permits, but does not require, specification of [[stereoisomer]]s.

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Bond direction symbols always come in groups of at least two, of which the first is arbitrary. That is, <code>F\C=C\F</code> is the same as <code>F/C=C/F</code>. 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 <code>C/C=C/C=C/C</code>.

[[File:Beta-Carotene_conjugation.svg|thumb|right|class=skin-invert-image|upright=0.866|[[Beta-carotene]], with the eleven double bonds highlighted.]]

As a more complex example, [[beta-carotene]] has a very long backbone of alternating single and double bonds, which may be written <code>CC1CCC/C(C)=C1/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)/CCCC2(C)C</code>.

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===Isotopes===

[[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 <code>[14c14cH]1ccccc1</code> and [[deuterochloroform]] is <code>[2H]C(Cl)(Cl)Cl</code>.

=== Examples ===

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|-----

|[[Methyl isocyanate]] (MIC)

|[[File:Methyl isocyanate.svg|frameless|120px|class=skin-invert-image]]

|CH₃−N=C=O

|<code>CN=C=O</code>

|-----

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|-----

|[[Vanillin]]

|[[Image:Vanillin.svg|class=skin-invert-image|70px|Molecular structure of vanillin]]

|<code>O=Cc1ccc(O)c(OC)c1</code><br/><code>COc1cc(C=O)ccc1O</code>

|-----

|[[Melatonin]] (C₁₃H₁₆N₂O₂)

|[[Image:Melatonin2.svg|class=skin-invert-image|160px|Molecular structure of melatonin]]

|<code>CC(=O)NCCC1=CNc2c1cc(OC)cc2</code><br/><code>CC(=O)NCCc1c[nH]c2ccc(OC)cc12</code>

|-----

|[[Flavopereirin]] (C₁₇H₁₅N₂)

|[[Image:Flavopereirine.svg|class=skin-invert-image|160px|Molecular structure of flavopereirin]]

|<code>CCc(c1)ccc2[n+]1ccc3c2[nH]c4c3cccc4</code><br/><code>CCc1c[n+]2ccc3c4ccccc4[nH]c3c2cc1</code>

|-----

|[[Nicotine]] (C₁₀H₁₄N₂)

|[[Image:Nicotine.svg|class=skin-invert-image|80px|Molecular structure of nicotine]]

|<code>CN1CCC[C@H]1c2cccnc2</code>

|-----

|[[Oenanthotoxin]] (C₁₇H₂₂O₂)

|[[Image:Oenanthotoxin-structure.png|class=skin-invert-image|180px|Molecular structure of oenanthotoxin]]

|<code>CCC[C@@H](O)CC\C=C\C=C\C#CC#C\C=C\CO</code><br/><code>CCC[C@@H](O)CC/C=C/C=C/C#CC#C/C=C/CO</code>

|-----

|[[Pyrethrin]] II (C₂₂H₂₈O₅)

|[[Image:Pyrethrin-II-2D-skeletal.svg|class=skin-invert-image|180px|Molecular structure of pyrethrin II]]

|<code>CC1=C(C(=O)C[C@@H]1OC(=O)[C@@H]2[C@H](C2(C)C)/C=C(\C)/C(=O)OC)C/C=C\C=C</code>

|-----

|[[Aflatoxin]] B₁ (C₁₇H₁₂O₆)

|[[Image:Aflatoxin B1.svg|class=skin-invert-image|130px|Molecular structure of aflatoxin B₁]]

|<code>O1C=C[C@H]([C@H]1O2)c3c2cc(OC)c4c3OC(=O)C5=C4CCC(=O)5</code>

|-----

|[[Glucose]] (β-<small>D</small>-glucopyranose) (C₆H₁₂O₆)

|[[Image:Beta-D-Glucose.svg|class=skin-invert-image|140px|Molecular structure of glucopyranose]]

|<code>OC[C@@H](O1)[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)1</code>

|-----

|[[Bergenin]] (cuscutin, a [[resin]]) (C₁₄H₁₆O₉)

|[[Image:Cuscutine.svg|class=skin-invert-image|130px|Molecular structure of cuscutine (bergenin)]]

|<code>OC[C@@H](O1)[C@@H](O)[C@H](O)[C@@H]2[C@@H]1c3c(O)c(OC)c(O)cc3C(=O)O2</code>

|-----

|A [[pheromone]] of the Californian [[scale insect]]

|[[Image:Pheromone cochenille californienne.svg|class=skin-invert-image|180px|(3''Z'',6''R'')-3-methyl-6-(prop-1-en-2-yl)deca-3,9-dien-1-yl acetate]]

|<code>CC(=O)OCCC(/C)=C\C[C@H](C(C)=C)CCC=C</code>

|-----

|(2''S'',5''R'')-[[Chalcogran]]: a [[pheromone]] of the [[Scolytinae|bark beetle]] ''[[Pityogenes chalcographus]]''<ref>{{cite journal | vauthors = Byers JA, Birgersson G, Löfqvist J, Appelgren M, Bergström G | title = Isolation of pheromone synergists of bark beetle, Pityogenes chalcographus, from complex insect-plant odors by fractionation and subtractive-combination bioassay | journal = Journal of Chemical Ecology | volume = 16 | issue = 3 | pages = 861–876 | date = March 1990 | pmid = 24263601 | doi = 10.1007/BF01016496 | bibcode = 1990JCEco..16..861B | s2cid = 226090 }}</ref>

|[[Image:2S,5R-chalcogran-skeletal.svg|class=skin-invert-image|130px|(2''S'',5''R'')-2-ethyl-1,6-dioxaspiro[4.4]nonane]]

|<code>CC[C@H](O1)CC[C@@]12CCCO2</code>

|-----

|[[Thujone|α-Thujone]] (C₁₀H₁₆O)

|[[Image:Alpha-thujone.svg|class=skin-invert-image|100px|Molecular structure of thujone]]

|<code>CC(C)[C@@]12C[C@@H]1[C@@H](C)C(=O)C2</code>

|-----

|[[Thiamine]] (vitamin B₁, C₁₂H₁₇N₄OS⁺)

|[[Image:Thiamin.svg|class=skin-invert-image|150px|Molecular structure of thiamin]]

|<code>OCCc1c(C)[n+](cs1)Cc2cnc(C)nc2N</code>

|}

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To illustrate a molecule with more than 9 rings, consider [[cephalostatin]]-1,<ref name="PubChem-183413">{{cite web |title=CID 183413 |url=https://pubchem.ncbi.nlm.nih.gov/compound/183413 |website=[[PubChem]] |access-date=May 12, 2012 |language=en}}</ref> a steroidic 13-ringed [[pyrazine]] with the [[empirical formula]] C₅₄H₇₄N₂O₁₀ isolated from the [[Indian Ocean]] [[hemichordate]] ''[[Cephalodiscus gilchristi]]'':

{{Clear}}

:[[Image:Cephalostatine-1.svg|class=skin-invert-image|360px|Molecular structure of cephalostatin-1]]

Starting with the left-most methyl group in the figure:

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:<code>CC(C)(O1)C[C@@H](O)[C@@]1(O2)[C@@H](C)[C@@H]3CC=C4[C@]3(C2)C(=O)C[C@H]5[C@H]4CC[C@@H](C6)[C@]5(C)Cc(n7)c6nc(C[C@@]89(C))c7C[C@@H]8CC[C@@H]%10[C@@H]9C[C@@H](O)[C@@]%11(C)C%10=C[C@H](O%12)[C@]%11(O)[C@H](C)[C@]%12(O%13)[C@H](O)C[C@@]%13(C)CO</code>

Note that <code>%</code> appears in front of the index of ring closure labels above 9; see {{Section link||Rings}} above.

=== Other examples of SMILES ===

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[[Smiles arbitrary target specification|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 character|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 [[Glossary of graph theory#Subgraphs|subgraph]] [[isomorphism]].

{{anchor|SMIRKS}}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 <code>REACTANT&gt;AGENT&gt;PRODUCT</code> (without spaces), where any of the fields can either be left blank or filled with multiple molecules deliminateddelineated with a dot (<code>.</code>), and other descriptions dependent on the base language. Atoms can additionally be identified with a number (e.g. <code>[C:1]</code>) for mapping,<ref>{{cite web |title=SMIRKS Tutorial |url=http://daylight.com/dayhtml_tutorials/languages/smirks/ | publisher = Daylight Chemical Information Systems, Inc. |access-date=29 October 2018}}</ref> for example in .<ref>{{cite web |title=Reaction SMILES and SMIRKS |url=http://www.daylight.com/meetings/summerschool01/course/basics/smirks.html |access-date = 29 October 2018 | publisher = Daylight Chemical Information Systems, Inc. }}</ref>

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.<ref>{{cite journal | vauthors = Lin TS, Coley CW, Mochigase H, Beech HK, Wang W, Wang Z, Woods E, Craig SL, Johnson JA, Kalow JA, Jensen KF, Olsen BD | display-authors = 6 | title = BigSMILES: A Structurally-Based Line Notation for Describing Macromolecules | journal = ACS Central Science | volume = 5 | issue = 9 | pages = 1523–1531 | date = September 2019 | pmid = 31572779 | pmc = 6764162 | doi = 10.1021/acscentsci.9b00476 }}</ref>

== Conversion ==

SMILES can be converted back to two-dimensional representations using structure diagram generation (SDG) algorithms.<ref name="Helson-1999">{{cite book | vauthors = Helson HE | year = 1999 | chapter = Structure Diagram Generation | title = Reviews in Computational Chemistry | veditors = Lipkowitz KB, Boyd DB |___location=New York |pages=313–398 |publisher=Wiley-VCH |doi=10.1002/9780470125908.ch6 |volume=13 | isbn = 978-0-470-12590-8 }}</ref> This conversion is notsometimes always unambiguousambiguous. Conversion to three-dimensional representation is achieved by energy-minimization approaches. There are many downloadable and web-based conversion utilities.

== See also ==

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== References ==

{{Reflist|33em}}

{{Molecular visualization}}