{"id":3059,"date":"2022-04-20T12:32:46","date_gmt":"2022-04-20T11:32:46","guid":{"rendered":"https:\/\/nextmovesoftware.com\/blog\/?p=3059"},"modified":"2025-09-22T09:47:14","modified_gmt":"2025-09-22T08:47:14","slug":"cxsmiles-part-2-component-grouping","status":"publish","type":"post","link":"https:\/\/nextmovesoftware.com\/blog\/2022\/04\/20\/cxsmiles-part-2-component-grouping\/","title":{"rendered":"CXSMILES Part 2: Component Grouping"},"content":{"rendered":"\n

This post is a follow up on the previous introduction – Part 1<\/a>. Here I examine how we can capture fragment grouping in CXSMILES and other extensions.<\/p>\n\n\n\n

Fragment Grouping<\/strong><\/h2>\n\n\n\n

Fragment grouping (or component grouping) allows you group together separate fragments\/components<\/a> of a molecule. It is critical for reaction representation and therefore several independent SMILES extensions that have emerged. Common cases include keeping counter-ions, hydrates, and salts together as a single “molecule”.<\/p>\n\n\n\n

\"\"<\/a>
EP2305640A2 Example 11, Step v<\/code>
(SMILES)<\/figcaption><\/figure><\/div>\n\n\n\n
\"\"<\/a>
EP2305640A2 Example 11, Step v<\/code>
(CXSMILES with fragment grouping)<\/figcaption><\/figure><\/div>\n\n\n\n

Syntax<\/strong><\/p>\n\n\n\n

Here is a simple example annotated with the fragment indexes, we want to group together (0,1) <\/code>and (3,4,5)<\/code>:<\/p>\n\n\n\n

[Na+].[OH-].c1ccccc1.[Cs+].[O-]C(=O)[O-].[Cs+]>> |f:0.1,3.4.5|\n--0-- --1-- ----2--- --3-- -----4------- --5--<\/code><\/pre>\n\n\n\n
Component indexes span the entire reaction, so we can for example move to the agents and the CXSMILES encoding does not change:<\/p>\n\n\n\n
[Na+].[OH-].c1ccccc1>[Cs+].[O-]C(=O)[O-].[Cs+]> |f:0.1,3.4.5|\n--0-- --1-- ----2--- --3-- -----4------- --5--<\/code><\/pre>\n\n\n\n
Does it only apply to reactions?<\/em> <\/strong><\/p>\n\n\n\n
Toolkit dependent<\/strong>. ChemAxon appears to only read\/write it on reactions (MarvinJS v22.9.0) but it’s also useful on molecules to capture formulations\/mixtures (e.g. Artifical seawater<\/a>) . In reaction, fragment grouping of agents (between the two “>”) appears to be ignored in MarvinJS – so my example images aren’t valid examples. One of our customers tested Marvin Desktop v21.15.1 for me and confirmed it round-trips correctly. <\/p>\n\n\n\n
Do component terms need to be adjacent?<\/em> <\/strong><\/p>\n\n\n\n
Toolkit dependent<\/strong>.<\/strong> In older versions of ChemAxon desktop tools (I no longer have access) I remember it would reject non-adjacent components:<\/p>\n\n\n\n
[Na+].c1ccccc1.[OH-]>> |f:0.2|<\/code><\/pre>\n\n\n\n
This does not seem to be the case in MarvinJS and again a customer again confirmed it round-trips ok in Marvin Desktop.<\/p>\n\n\n\n
Spanning Different Roles?<\/em> <\/strong><\/p>\n\n\n\n
An input where the roles of the components being grouped (e.g. a reactant and a product) could be rejected as inconsistent:<\/p>\n\n\n\n
c1ccccc1.[Na+]>>[OH-] |f:1.2|\nc1ccccc1.[Na+]>>[OH-] |f:2.1|<\/code><\/pre>\n\n\n\n
MarvinJS and CDK default to the role of the first component encountered so those two inputs are different. As the author of the CDK logic I will note this is consistent only by coincidence. <\/p>\n\n\n\n
Implicit grouping?<\/em><\/strong><\/p>\n\n\n\n
We can implicitly group components with multi-attach (m:<\/strong>) and Sgroup brackets. For example consider the following, which is preferred?<\/p>\n\n\n\n
\"\"<\/a><\/figure><\/div>\n\n\n\n
**.c1ccccc1 |$R1$,m:1:2.3.4.5.6.7|\n**.c1ccccc1 |$R1$,f:0.1,m:1:2.3.4.5.6.7|<\/code><\/pre>\n\n\n\n
Alternatives<\/h2>\n\n\n\n
Daylight SMILES5<\/strong><\/p>\n\n\n\n
As with the cis\/trans specification, SMILES5 had a solution: <\/p>\n\n\n\n
“Molecule-level Components: There will be another level of components within a molecule and reaction object which will allow easier handling of complex mixtures.<\/em>” – Futures, MUG 2005<\/a><\/p>\n\n\n\n
SMARTS has component grouping using zero-level brackets already and it would likely have followed a similar syntax:<\/p>\n\n\n\n
([Na+].[OH-]).c1ccccc1.([Cs+].[O-]C(=O)[O-].[Cs+])>><\/code><\/pre>\n\n\n\n
Notice the wording that it applies to both molecule and reactions<\/strong>.<\/p>\n\n\n\n
LillyMol<\/strong><\/p>\n\n\n\n
An extension used by Eli Lilly’s LillyMol<\/a> is to treat the “.” to separate fragments and use a “+” to separate the molecules<\/a>.<\/p>\n\n\n\n
[Na+].[OH-]+c1ccccc1+[Cs+].[O-]C(=O)[O-].[Cs+]>><\/code><\/pre>\n\n\n\n
Note that LillyMol also supports CXSMILES.<\/p>\n\n\n\n
IBM RXN for Chemistry<\/strong><\/p>\n\n\n\n
Schwaller et al<\/em> 2020<\/a> describe how they use “~” to group together fragments. They note in the supplementary information how this is more useful than CXSMILES for their purposes since it enforces the fragments are kept together:<\/p>\n\n\n\n
[Na+]~[OH-].c1ccccc1.[Cs+]~[O-]C(=O)[O-]~[Cs+]>><\/code><\/pre>\n\n\n\n
NextMove (proposed) \/ OntoChem<\/strong><\/p>\n\n\n\n
In 2013 Roger proposed a double-dot <\/a>“..” for a similar purpose. The advantage being that “relaxed” SMILES parsers will simply ignore the repeated dot:<\/p>\n\n\n\n
[Na+]..[OH-].c1ccccc1.[Cs+]..[O-]C(=O)[O-]..[Cs+]>><\/code><\/pre>\n\n\n\n
OntoChem<\/a> also use this representation in reactions but I cannot find a link to relevant material.<\/p>\n\n\n\n
NextMove (actual)<\/strong><\/p>\n\n\n\n
In Pistachio<\/a> we use CXSMILES for fragment grouping in reactions. In recent releases<\/a> we have tried to use alternative representations that avoid the problem where possible:<\/p>\n\n\n\n
[Na]O.c1ccccc1.[Cs]OC(=O)O[Cs]>><\/code><\/pre>\n\n\n\n
Where needed we still use CXSMILES since it is the most widely supported convention:<\/p>\n\n\n\n
\"\"<\/a>
HATU reagent<\/figcaption><\/figure><\/div>\n\n\n\n
\"\"<\/a>
US20200138797A1 Intermediate 3<\/figcaption><\/figure><\/div>\n\n\n\n
The fragment grouping also gets captured in the JSON format of reactions albeit much less compactly:<\/p>\n\n\n\n
{\nrole: "Product",\norgName: "title compound",\nname: "Methyl (2S)-2-amino-3-(2-chlorophenyl)propanoate hydrochloride",\nsmiles: "Cl.N[C@H](C(=O)OC)CC1=C(C=CC=C1)Cl",\nquantities: [ {type: "Mass", value: 5.89, text: "5.89 g"},\n              {type: "Yield", value: 94, text: "94%"}],\nstoichiometry: 1\n}<\/code><\/pre><\/div>\n\n\n\n
We also support interconversion of the LillyMol syntax in our reaction processing tool set, HazELNut<\/a>:<\/p>\n\n\n\n
$ echo \"*>[Na+].[OH-].[Cs+].[O-]C(=O)[O-].[Cs+]>* |f:1.2.3,4.5|\" | .\/filbert .smi .iwsmi\n*>C(=O)([O-])[O-].[Cs+]+[OH-].[Na+].[Cs+]>*\n\n$ echo \"*>C(=O)([O-])[O-].[Cs+]+[OH-].[Na+].[Cs+]>*\" | .\/filbert .iwsmi .smi\n*>C(=O)([O-])[O-].[OH-].[Na+].[Cs+].[Cs+]>* |f:1.4,2.3.5| <\/code><\/pre>\n","protected":false},"excerpt":{"rendered":"
This post is a follow up on the previous introduction – Part 1. Here I examine how we can capture fragment grouping in CXSMILES and other extensions. Fragment Grouping Fragment grouping (or component grouping) allows you group together separate fragments\/components of a molecule. It is critical for reaction representation and therefore several independent SMILES extensions … Continue reading CXSMILES Part 2: Component Grouping<\/span><\/a><\/p>\n","protected":false},"author":5,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[24,26,23,25],"tags":[],"_links":{"self":[{"href":"https:\/\/nextmovesoftware.com\/blog\/wp-json\/wp\/v2\/posts\/3059"}],"collection":[{"href":"https:\/\/nextmovesoftware.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/nextmovesoftware.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/nextmovesoftware.com\/blog\/wp-json\/wp\/v2\/users\/5"}],"replies":[{"embeddable":true,"href":"https:\/\/nextmovesoftware.com\/blog\/wp-json\/wp\/v2\/comments?post=3059"}],"version-history":[{"count":45,"href":"https:\/\/nextmovesoftware.com\/blog\/wp-json\/wp\/v2\/posts\/3059\/revisions"}],"predecessor-version":[{"id":3147,"href":"https:\/\/nextmovesoftware.com\/blog\/wp-json\/wp\/v2\/posts\/3059\/revisions\/3147"}],"wp:attachment":[{"href":"https:\/\/nextmovesoftware.com\/blog\/wp-json\/wp\/v2\/media?parent=3059"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/nextmovesoftware.com\/blog\/wp-json\/wp\/v2\/categories?post=3059"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/nextmovesoftware.com\/blog\/wp-json\/wp\/v2\/tags?post=3059"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}