TheSimplified Molecular Input Line Entry System(SMILES) is a specification in the form of aline notationfor describing the structure ofchemical speciesusing shortASCIIstrings.SMILES strings can be imported by mostmolecule editorsfor conversion back intotwo-dimensionaldrawings orthree-dimensionalmodels of the molecules.
| Filename extension |
.smi |
|---|---|
| Internet media type |
chemical/x-daylight-smiles |
| Type of format | chemical file format |
The original SMILES specification was initiated in the 1980s. It has since been modified and extended. In 2007, anopen standardcalled OpenSMILES was developed in theopen sourcechemistry community.
History
editThe original SMILES specification was initiated byDavid Weiningerat the USEPA Mid-Continent Ecology Division Laboratory inDuluthin the 1980s.[1][2][3][4]Acknowledged for their parts in the early development were "Gilman Veith and Rose Russo (USEPA) and Albert Leo andCorwin 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. "[5]TheEnvironmental Protection Agencyfunded the initial project to develop SMILES.[6][7]
It has since been modified and extended by others, most notably byDaylight Chemical Information Systems.In 2007, anopen standardcalled "OpenSMILES" was developed by theBlue Obeliskopen-source chemistry community. Other 'linear' notations include theWiswesser Line Notation(WLN),ROSDALandSLN(Tripos Inc).
In July 2006, theIUPACintroduced theInChIas 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 asgraph theory).
Terminology
editThe 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,OCCandC(O)Call specify the structure ofethanol.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 thecanonicalizationalgorithm 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,MolSoftLLC, and theChemistry Development Kit.A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in adatabase.
The original paper that described the CANGEN[2]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.[8]There is currently no systematic comparison across commercial software to test if such flaws exist in those packages.
SMILES notation allows the specification ofconfiguration 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 whichisomersare specified.
Graph-based definition
editIn terms of a graph-based computational procedure, SMILES is a string obtained by printing the symbol nodes encountered in adepth-firsttree traversalof achemical graph.The chemical graph is first trimmed to remove hydrogen atoms and cycles are broken to turn it into aspanning 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
editFrom 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 andbiodegradability) 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)[9]as well as a more robust scheme based on statistical pattern recognition.[10]
Description
editAtoms
editAtomsare represented by the standard abbreviation of thechemical elements,in square brackets, such as[Au]forgold.Brackets may be omitted in the common case of atoms which:
- are in the "organic subset"ofB,C,N,O,P,S,F,Cl,Br,orI,and
- have noformal 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 normalisotopes,and
- are notchiral centers.
All other elements must be enclosed in brackets, and have charges and hydrogens shown explicitly. For instance, the SMILES forwatermay be written as eitherOor[OH2].Hydrogen may also be written as a separate atom; water may also be written as[H]O[H].
When brackets are used, the symbolHis 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,[NH4+]forammonium(NH+
4). 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[Ti+4]or[Ti++++]fortitanium(IV) Ti4+.Thus, thehydroxideanion( OH−) is represented by[OH-],thehydroniumcation (H3O+) is[OH3+]and thecobalt(III)cation(Co3+) is either[Co+3]or[Co+++].
Bonds
editA bond is represented using one of the symbols.- = # $: / \.
Bonds betweenaliphaticatoms are assumed to be single unless specified otherwise and are implied by adjacency in the SMILES string. Although single bonds may be written as-,this is usually omitted. For example, the SMILES forethanolmay be written asC-C-O,CC-OorC-CO,but is usually writtenCCO.
Double, triple, and quadruplebondsare represented by the symbols=,#,and$respectively as illustrated by the SMILESO=C=O(carbon dioxideCO2),C#N(hydrogen cyanideHCN) 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, aqueoussodium chloridemay be written as[Na+].[Cl-]to show the dissociation.
An aromatic "one and a half" bond may be indicated with:;see§ Aromaticitybelow.
Single bonds adjacent to double bonds may be represented using/or\to indicate stereochemical configuration; see§ Stereochemistrybelow.
Rings
editRing 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 anacyclicstructure and adding numerical ring closure labels to show connectivity between non-adjacent atoms.
For example,cyclohexaneanddioxanemay be written asC1CCCCC1andO1CCOCC1respectively. For a second ring, the label will be 2. For example,decalin(decahydronaphthalene) may be written asC1CCCC2C1CCCC2.
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,bicyclohexylis usually written asC1CCCCC1C2CCCCC2,but it may also be written asC0CCCCC0C0CCCCC0.
Multiple digits after a single atom indicate multiple ring-closing bonds. For example, an alternative SMILES notation for decalin isC1CCCC2CCCCC12,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%,soC%12is 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,cyclopropeneis usually writtenC1=CC1,but if the double bond is chosen as the ring-closing bond, it may be written asC=1CC1,C1CC=1,orC=1CC=1.(The first form is preferred.)C=1CC-1is 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,C1C1is not a valid alternative toC=Cforethylene.However, they may be used with non-bonds;C1.C2.C12is a peculiar but legal alternative way to writepropane,more commonly writtenCCC.
Choosing a ring-break point adjacent to attached groups can lead to a simpler SMILES form by avoiding branches. For example,cyclohexane-1,2-diolis most simply written asOC1CCCCC1O;choosing a different ring-break location produces a branched structure that requires parentheses to write.
Aromaticity
editAromaticrings such asbenzenemay be written in one of three forms:
- InKekuléform with alternating single and double bonds, e.g.
C1=CC=CC=C1, - Using the aromatic bond symbol
:,e.g.C:1:C:C:C:C:C1,or - Most commonly, by writing the constituent B, C, N, O, P and S atoms in lower-case forms
b,c,n,o,pands,respectively.
In the latter case, bonds between two aromatic atoms are assumed (if not explicitly shown) to be aromatic bonds. Thus,benzene,pyridineandfurancan be represented respectively by the SMILESc1ccccc1,n1ccccc1ando1cccc1.
Aromatic nitrogen bonded to hydrogen, as found inpyrrolemust be represented as[nH];thusimidazoleis written in SMILES notation asn1c[nH]cc1.
When aromatic atoms are singly bonded to each other, such as inbiphenyl,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 formc1ccccc1c2ccccc2.)
The Daylight and OpenEye algorithms for generating canonical SMILES differ in their treatment of aromaticity.
COc(c1)cccc1C#N.Branching
editBranches are described with parentheses, as inCCC(=O)Oforpropionic acidandFC(F)Fforfluoroform.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 SMILESCOc(c1)cccc1C#N(see depiction) andCOc(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,bromochlorodifluoromethanemay be written asFC(Br)(Cl)F,BrC(F)(F)Cl,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§ Stereochemistrybelow.
The one form of branch which doesnotrequire parentheses are ring-closing bonds: the SMILES fragmentC1Nis equivalent toC(1)N,both denoting a bond between theCand theN.Choosing ring-closing bonds adjacent to branch points can reduce the number of parentheses required. For example,tolueneis normally written asCc1ccccc1orc1ccccc1C,avoiding the parentheses required if written asc1cc(C)ccc1orc1cc(ccc1)C.
Stereochemistry
edit
SMILES permits, but does not require, specification ofstereoisomers.
Configuration around double bonds is specified using the characters/and\to show directional single bonds adjacent to a double bond. For example,F/C=C/F(see depiction) is one representation oftrans-1,2-difluoroethylene,in which the fluorine atoms are on opposite sides of the double bond (as shown in the figure), whereasF/C=C\F(see depiction) is one possible representation ofcis-1,2-difluoroethylene, in which the fluorines are on the same side of the double bond.
Bond direction symbols always come in groups of at least two, of which the first is arbitrary. That is,F\C=C\Fis the same asF/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 writtenC/C=C/C=C/C.
As a more complex example,beta-carotenehas a very long backbone of alternating single and double bonds, which may be writtenCC1CCC/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.
Configuration attetrahedral carbonis specified by@or@@.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@@and@,respectively (because the@symbol itself is a counter-clockwise spiral).
For example, consider theamino acidalanine.One of its SMILES forms isNC(C)C(=O)O,more fully written asN[CH](C)C(=O)O.L-Alanine,the more commonenantiomer,is written asN[C@@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 asN[C@H](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 asNC(C(=O)O)C,then the configuration also reverses;L-alanine is written asN[C@H](C(=O)O)C(see depiction). Other ways of writing it includeC[C@H](N)C(=O)O,OC(=O)[C@@H](N)CandOC(=O)[C@H](C)N.
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 asC(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[C@@H](C)(N)C(=O)O.
The SMILES specification includes elaborations on the@symbol to indicate stereochemistry around more complex chiral centers, such astrigonal bipyramidal molecular geometry.
Isotopes
editIsotopesare specified with a number equal to the integer isotopic mass preceding the atomic symbol.Benzenein which one atom iscarbon-14is written as[14c]1ccccc1anddeuterochloroformis[2H]C(Cl)(Cl)Cl.
Examples
edit| Molecule | Structure | SMILES formula |
|---|---|---|
| Dinitrogen | N≡N | N#N
|
| Methyl isocyanate(MIC) | CH3−N=C=O | CN=C=O
|
| Copper(II) sulfate | Cu2+SO2− 4 |
[Cu+2].[O-]S(=O)(=O)[O-]
|
| Vanillin | 
|
O=Cc1ccc(O)c(OC)c1COc1cc(C=O)ccc1O
|
| Melatonin(C13H16N2O2) | 
|
CC(=O)NCCC1=CNc2c1cc(OC)cc2CC(=O)NCCc1c[nH]c2ccc(OC)cc12
|
| Flavopereirin(C17H15N2) | 
|
CCc(c1)ccc2[n+]1ccc3c2[nH]c4c3cccc4CCc1c[n+]2ccc3c4ccccc4[nH]c3c2cc1
|
| Nicotine(C10H14N2) | 
|
CN1CCC[C@H]1c2cccnc2
|
| Oenanthotoxin(C17H22O2) | 
|
CCC[C@@H](O)CC\C=C\C=C\C#CC#C\C=C\COCCC[C@@H](O)CC/C=C/C=C/C#CC#C/C=C/CO
|
| PyrethrinII (C22H28O5) | 
|
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
|
| AflatoxinB1(C17H12O6) | 
|
O1C=C[C@H]([C@H]1O2)c3c2cc(OC)c4c3OC(=O)C5=C4CCC(=O)5
|
| Glucose(β-D-glucopyranose) (C6H12O6) | 
|
OC[C@@H](O1)[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)1
|
| Bergenin(cuscutin, aresin) (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
|
| Apheromoneof the Californianscale insect | 
|
CC(=O)OCCC(/C)=C\C[C@H](C(C)=C)CCC=C
|
| (2S,5R)-Chalcogran:apheromoneof thebark beetlePityogenes chalcographus[11] | ![(2S,5R)-2-ethyl-1,6-dioxaspiro[4.4]nonane](/translate/en.m.wikipedia.org?u=https%3A%2F%2Fen.m.wikipedia.org%2Fwiki%2FFile%3A2S%2C5R-chalcogran-skeletal.svg&t=hv)
|
CC[C@H](O1)CC[C@@]12CCCO2
|
| α-Thujone(C10H16O) | 
|
CC(C)[C@@]12C[C@@H]1[C@@H](C)C(=O)C2
|
| Thiamine(vitamin B1,C12H17N4OS+) | 
|
OCCc1c(C)[n+](cs1)Cc2cnc(C)nc2N
|
To illustrate a molecule with more than 9 rings, considercephalostatin-1,[12]a steroidic 13-ringedpyrazinewith theempirical formulaC54H74N2O10isolated from theIndian OceanhemichordateCephalodiscus gilchristi:
Starting with the left-most methyl group in the figure:
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
%appears in front of the index of ring closure labels above 9; see§ Ringsabove.
Other examples of SMILES
editThe 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.
Extensions
editSMARTSis a line notation for specification of substructural patterns in molecules. While it uses many of the same symbols as SMILES, it also allows specification ofwildcardatoms and bonds, which can be used to define substructural queries forchemical databasesearching. 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 forsubgraphisomorphism.
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 isREACTANT>AGENT>PRODUCT(without spaces), where any of the fields can either be left blank or filled with multiple molecules delineated 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,[13]for example in.[14]
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.[15]
Conversion
editSMILES can be converted back to two-dimensional representations using structure diagram generation (SDG) algorithms.[16]This conversion is sometimes ambiguous. Conversion to three-dimensional representation is achieved by energy-minimization approaches. There are many downloadable and web-based conversion utilities.
See also
edit- SMILES arbitrary target specification(SMARTS), an extension of SMILES for specification of substructural queries
- SYBYL Line Notation,another line notation
- International Chemical Identifier(InChI), theIUPAC's alternative to SMILES
- Molecular Query Language,aquery languageallowing also numerical properties, e.g. physicochemical values or distances
- Chemistry Development Kit,2D layout and conversion software
- OpenBabel,JOELib,OELib(conversion)
References
edit- ^Weininger D (February 1988). "SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules".Journal of Chemical Information and Computer Sciences.28(1): 31–6.doi:10.1021/ci00057a005.
- ^abWeininger D, Weininger A, Weininger JL (May 1989). "SMILES. 2. Algorithm for generation of unique SMILES notation".Journal of Chemical Information and Modeling.29(2): 97–101.doi:10.1021/ci00062a008.
- ^Weininger D (August 1990). "SMILES. 3. DEPICT. Graphical depiction of chemical structures".Journal of Chemical Information and Modeling.30(3): 237–43.doi:10.1021/ci00067a005.
- ^Swanson RP (2004)."The Entrance of Informatics into Combinatorial Chemistry"(PDF).In Rayward WB, Bowden ME (eds.).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.Medford, NJ:Information Today.p. 205.ISBN978-1-57387-229-4.
- ^Weininger D (1998)."Acknowledgements on Daylight Tutorial smiles-etc page".RetrievedJune 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 fromthe originalon March 28, 2008.RetrievedSeptember 23,2012.
- ^Neglur G, Grossman RL, Liu B (2005)."Assigning Unique Keys to Chemical Compounds for Data Integration: Some Interesting Counter Examples".In Ludäscher B (ed.).Data Integration in the Life Sciences.Lecture Notes in Computer Science. Vol. 3615. Berlin: Springer. pp. 145–157.doi:10.1007/11530084_13.ISBN978-3-540-27967-9.RetrievedFebruary 12,2013.
- ^Sidorova J, Anisimova M (August 2014). "NLP-inspired structural pattern recognition in chemical application".Pattern Recognition Letters.45:11–16.Bibcode:2014PaReL..45...11S.doi:10.1016/j.patrec.2014.02.012.
- ^Sidorova J, Garcia J (November 2015). "Bridging from syntactic to statistical methods: Classification with automatically segmented features from sequences".Pattern Recognition.48(11): 3749–3756.Bibcode:2015PatRe..48.3749S.doi:10.1016/j.patcog.2015.05.001.hdl:10016/33552.
- ^Byers JA, Birgersson G, Löfqvist J, Appelgren M, Bergström G (March 1990). "Isolation of pheromone synergists of bark beetle, Pityogenes chalcographus, from complex insect-plant odors by fractionation and subtractive-combination bioassay".Journal of Chemical Ecology.16(3): 861–876.doi:10.1007/BF01016496.PMID24263601.S2CID226090.
- ^"CID 183413".PubChem.RetrievedMay 12,2012.
- ^"SMIRKS Tutorial".Daylight Chemical Information Systems, Inc.RetrievedOctober 29,2018.
- ^"Reaction SMILES and SMIRKS".Daylight Chemical Information Systems, Inc.RetrievedOctober 29,2018.
- ^Lin TS, Coley CW, Mochigase H, Beech HK, Wang W, Wang Z, et al. (September 2019)."BigSMILES: A Structurally-Based Line Notation for Describing Macromolecules".ACS Central Science.5(9): 1523–1531.doi:10.1021/acscentsci.9b00476.PMC6764162.PMID31572779.
- ^Helson HE (1999). "Structure Diagram Generation". In Lipkowitz KB, Boyd DB (eds.).Reviews in Computational Chemistry.Vol. 13. New York: Wiley-VCH. pp. 313–398.doi:10.1002/9780470125908.ch6.ISBN978-0-470-12590-8.