| SMILES | |
|---|---|
| Filename extension | .smi |
| Internet media type | chemical/x-daylight-smiles |
| Type of format | chemical file format |
TheSimplified Molecular Input Line Entry System (SMILES) is a specification in the form of aline notation for describing the structure ofchemical species using shortASCIIstrings. SMILES strings can be imported by mostmolecule editors for conversion back intotwo-dimensional drawings orthree-dimensional models of the molecules.
The original SMILES specification was initiated in the 1980s. It has since been modified and extended. In 2007, anopen standard called OpenSMILES was developed in theopen source chemistry community.
The original SMILES specification was initiated byDavid Weininger at the USEPA Mid-Continent Ecology Division Laboratory inDuluth in 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 Agency funded 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 standard called "OpenSMILES" was developed by theBlue Obelisk open-source chemistry community. Other 'linear' notations include theWiswesser Line Notation (WLN),ROSDAL andSLN (Tripos Inc).
In July 2006, theIUPAC introduced theInChI 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 asgraph 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,CCO,OCC andC(O)C all 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 thecanonicalization 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 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 whichisomers are specified.
In terms of a graph-based computational procedure, SMILES is a string obtained by printing the symbol nodes encountered in adepth-firsttree traversal of 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:
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 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]
Atoms are 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:
All other elements must be enclosed in brackets, and have charges and hydrogens shown explicitly. For instance, the SMILES forwater may be written as eitherO or[OH2]. Hydrogen may also be written as a separate atom; water may also be written as[H]O[H].
When brackets are used, the symbolH 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,[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-], thehydronium cation (H3O+) is[OH3+] and thecobalt(III)cation (Co3+) is either[Co+3] or[Co+++].
A bond is represented using one of the symbols. - = # $ : / \.
Bonds betweenaliphatic 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 forethanol may be written asC-C-O,CC-O orC-CO, but is usually writtenCCO.
Double, triple, and quadruplebonds are represented by the symbols=,#, and$ respectively as illustrated by the SMILESO=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, aqueoussodium 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/ or\ 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 anacyclic structure and adding numerical ring closure labels to show connectivity between non-adjacent atoms.
For example,cyclohexane anddioxane may be written asC1CCCCC1 andO1CCOCC1 respectively. 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,bicyclohexyl is 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%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 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-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 toC=C forethylene. However, they may be used with non-bonds;C1.C2.C12 is 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-diol is most simply written asOC1CCCCC1O; choosing a different ring-break location produces a branched structure that requires parentheses to write.
Aromatic rings such asbenzene may be written in one of three forms:
C1=CC=CC=C1,:, e.g.C1:C:C:C:C:C1,[citation needed] orb,c,n,o,p ands, respectively.In the latter case, bonds between two aromatic atoms are assumed (if not explicitly shown) to be aromatic bonds. Thus,benzene,pyridine andfuran can be represented respectively by the SMILESc1ccccc1,n1ccccc1 ando1cccc1.
Aromatic nitrogen bonded to hydrogen, as found inpyrrole must be represented as[nH]; thusimidazole is 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.Branches are described with parentheses, as inCCC(=O)O forpropionic acid andFC(F)F forfluoroform. 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,bromochlorodifluoromethane may 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:
The one form of branch which doesnot require parentheses are ring-closing bonds: the SMILES fragmentC1N is equivalent toC(1)N, both denoting a bond between theC and theN. Choosing ring-closing bonds adjacent to branch points can reduce the number of parentheses required. For example,toluene is normally written asCc1ccccc1 orc1ccccc1C, avoiding the parentheses required if written asc1cc(C)ccc1 orc1cc(ccc1)C.
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\F is 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-carotene has 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 carbon is 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)C andOC(=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 are specified with a number equal to the integer isotopic mass preceding the atomic symbol.Benzene in which one atom iscarbon-14 is written as[14cH]1ccccc1 anddeuterochloroform is[2H]C(Cl)(Cl)Cl.
| Molecule | Structure | SMILES formula |
|---|---|---|
| Dinitrogen | N≡N | N#N |
| Methyl isocyanate (MIC) |  | 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 |
| Pyrethrin II (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 |
| Aflatoxin B1 (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 |
| Apheromone of the Californianscale insect |  | CC(=O)OCCC(/C)=C\C[C@H](C(C)=C)CCC=C |
| (2S,5R)-Chalcogran: apheromone of thebark beetlePityogenes chalcographus[11] | ![(2S,5R)-2-ethyl-1,6-dioxaspiro[4.4]nonane](/mt/?noimg=&dark=on&url=http%3a%2f%2fen.wikipedia.org%2fwiki%2fFile%3a2S%2c5R-chalcogran-skeletal.svg) | 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-ringedpyrazine with theempirical formula C54H74N2O10 isolated 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§ Rings above.
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 ofwildcard atoms and bonds, which can be used to define substructural queries forchemical 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 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]
SMILES 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.