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Advanced Stereochemistry Registration: Mixtures, Unknowns and Non-Tetrahedral Chirality

All chemistry within CDD Vault is handled via the ChemAxon chemistry engine. The general documentation for all things regarding ChemAxon can be found on their web-pages. Here the link to the documentation for handling of stereochemistry:

https://docs.chemaxon.com/display/docs/Stereochemistry+JCB

In general, molecules registered into CDD Vault containing “up” or “down” bonds are interpreted "as drawn". You can, however, represent racemic mixtures, pure enantiomers (both known and unknown configurations) using the V3000 enhanced stereochemical notation. ChemAxon documents these enhanced notations here:

https://docs.chemaxon.com/display/docs/Stereochemistry+JCB#StereochemistryJCB-mdl_enhanced_stereo

This annotation allows for registration of a single entity to describe stereochemical mixtures.  The alternative method to draw two or more enantiomers, leading to registration of multiple entities in a single record with properties reflecting the total number of all molecules.  This may lead to confusion since the fully drawn mixture of two entities would double the molecular mass. Using AND/OR annotations to register a single entity, will lead to expected molecular mass of only the one compound.

Here we demonstrate some implementations of these "AND" and "OR" enhanced stereochemical labels/designations.

As pointed out elsewhere in our Knowledge Base, stereochemical information is best dealt with as MOL (alt. SDF) format, instead of SMILES format due to the limitations of SMILES, especially with regards to mixtures. Therefore, we recommend drawing and registering a Molecule using the V3000 Enhanced Stereochemistry. Use the "AND" enhanced stereo label to indicate that the Molecule represents an isomeric mixture and the “OR” label to indicate cases for absolute, but unknown stereochemical centers.

With the Structure Editor in CDD Vault (MarvinJS), users can select the atom, right click, select Atom Properties and use the Enhanced Stereo options to add the labels.  These options should be available in most modern chemistry sketcher programs like MarvinSketch and ChemDraw.

Below we illustrate several examples to help users with visibility/understanding of registered compounds using these labels. This should also allow the otherwise difficult to achieve registration of sterically hindered amides, or other, non-tetrahedral chiral structures.

 The following represents a mixture of 4 diastereoisomers
mceclip1.png

and represents a mixture of all of the following 4 diastereoisomers

mceclip5.png mceclip2.png
mceclip4.png mceclip2.png

 The following represents a mixture of 2 enantiomers

mceclip0.png

and represents a mixture of the following 2 enantiomers

mceclip2.png mceclip2.png

The following represents a mixture of 2 enantiomers

mceclip0.png

and represents a mixture of the following 2 enantiomers

mceclip5.png mceclip4.png

The following represents a pure sample of unknown configuration
mceclip0.png

but is one of these 4 diastereoisomers

mceclip5.png mceclip2.png
mceclip4.png mceclip2.png

The following represents a pure sample of unknown absolute configuration

mceclip0.png

but is one of these 2 enantiomers

mceclip2.png mceclip2.png

 The following represents a pure sample unknown configuration

mceclip0.png

but is one of these 2 enantiomers

mceclip5.png mceclip4.png

 

Registering a Series of Duplicates with Unique Registration IDs

CDD Vault supports additional functionality within external drawing programs like MarvinSketch and ChemDraw to help with structure registrations that are problematic.

To register when using external Marvin Sketch, either save as MDL SDfile (V3000 will be created automatically) or copy/paste via “Copy as” and choose “MDL MOL file” and paste this into the text portion of the "Structure" section of the manual registration page (not into the built-in Marvin JS structure editor present in CDD Vault).  Similarly, in ChemDraw, users would select the option Edit - Copy As  - MOL V3000 Text and paste the contents into the "Structure" section of the manual registration page.

You will likely see a warning in the banner section stating that the the new molecule is a duplicate. This is expected behavior and can help for faster identification of related stereoisomers.

 

Example: one pure isomer, absolute unknown

Example based on external Marvin Sketch - in the case of having pure isomers, but not knowing the absolute configuration

1) For the racemate, don’t select wiggle bonds, simple draw a flat bond

2) For the first isomer: Don’t draw an up/down bond, use a flat bond instead. Select the corresponding stereocenter and choose “or1”. Then select the complete molecule, right-click and select “Add -> Data…”. Choose “Fragment” and call it e.g. “ISOMER” (without quotes). As value you can basically type anything you wish: e.g. “ISOMER 1, unknown absolute”. Choose “Relative” as (preferred) placement option.

3) For a second isomer, repeat this using “or2”, but in addition you will have to group the compound (select the structure, then either press CTRL-G on windows, or right-click to choose “Group…”). Choose “monomer (mon)”, alternatively “Repeating unit with repeating ranges” and add “1” as the range.

This allows to register e.g. these 5 versions of this molecule as separate entities:

Non-tetrahedral compounds are more complex to register, but it is possible to register with brackets (sterically hindered amide or axially chiral compounds are an example):

The procedure is the same as described in the previous section, for additional clarity you can add the “abs” feature to the Nitrogen (select the N, then right click and choose Stereo -> Enhanced -> abs).

Example: Axial chirality (non-tetrahedral chiral compound):

In the case of axial chirality, you will have to group each enantiomer, and you will have to group each in a different way. We suggest using “monomer” in one case and “repeating unit…. = 1” in the other.

For helicene type of compounds you would register them in the same way.

The important feature to remember for this type of registration is the usage of the “Group…” functionality. By choosing a different type of group each time, the registration system keeps entities apart, despite seeing them as potential duplicates.

Instructions for creating Brackets within Chemical Drawing Packages

If you are in need of generating duplicate registrations for 2 to 4 molecules, users can create the molecules using CDD Vault's built in chemistry editor, MarvinJS.  Here are the steps:

1) Draw the first molecule in MarvinJS and Register the structure.

2) For the first duplicate (molecule 2), draw the molecule again in MarvinJS.   Click the "Repeating Group" icon on the left toolbar.  Draw a box around the molecule and the Repeating Group box will appear.

Enter a "1" into the bottom box.  Register the molecule.

3) For the 2nd duplicate (molecule 3), Repeat Step 2 and change the top pull down box to "hh".  Register the molecule.

4) For the 3rd duplicate (molecule 4), Repeat Step 3 and change the top pull down box to "eu".  Register the molecule.

 

If you are in need of generating more that 4 duplicate registrations, you will need to use a 3rd party chemical editor like MarvinSketch or ChemDraw.

For ChemDraw v18, here are the steps to create molecules with different bracket combinations:

1) Draw the molecule

2) Click the "Brackets" icon on the main toolbar.  Extend the bracket so the entire molecule is within the bracket.

3) Mouse over the bracket and right click.  Select Bracket Usage, then "Monomer".  Right click again and select Repeat Pattern then "Head to Tail"

 

Our current testing should allow users to register up to 32 copies (duplicates) of the same molecule using the following combinations of Bracket Usage and Repeat Pattern.

 1) Base Molecule

2) MarvinJS - Repeating Groups - ht, n=1  OR   ChemDraw 18 - Bracket Usage = SRU, n=1 - Repeat Pattern = Head to Tail (default)

3)  MarvinJS - Repeating Group - hh - n=1  OR   ChemDraw 18 - Bracket Usage = SRU, n=1 - Repeat Pattern = Head to Head

4) MarvinJS - Repeating Group - eu - n=1  OR   ChemDraw 18 - Bracket Usage = SRU, n=1 - Repeat Pattern = Either/Unknown

5) ChemDraw 18 - Bracket Usage = Monomer - Repeat Pattern = Head to Tail (default)

6) ChemDraw 18 - Bracket Usage = Monomer - Repeat Pattern = Head to Head

7) ChemDraw 18 - Bracket Usage = Monomer - Repeat Pattern = Either/Unknown

8) ChemDraw 18 - Bracket Usage = Component - Repeat Pattern = any

9) ChemDraw 18 - Bracket Usage = Co Polymer - Repeat Pattern = Head to Tail (default)

10) ChemDraw 18 - Bracket Usage = Co Polymer - Repeat Pattern = Head to Head

11) ChemDraw 18 - Bracket Usage = Co Polymer - Repeat Pattern = Either/Unknown

12) ChemDraw 18 - Bracket Usage = Copolymer Alternating - Repeat Pattern = Head to Tail (default)

13) ChemDraw 18 - Bracket Usage = Copolymer Alternating - Repeat Pattern = Head to Head

14) ChemDraw 18 - Bracket Usage = Copolymer Alternating - Repeat Pattern = Either/Unknown

15)  ChemDraw 18 - Bracket Usage = Copolymer Block - Repeat Pattern = Head to Tail (default)

16) ChemDraw 18 - Bracket Usage = Copolymer Block - Repeat Pattern = Head to Head

17) ChemDraw 18 - Bracket Usage = Copolymer Block - Repeat Pattern = Either/Unknown

18) ChemDraw 18 - Bracket Usage = Copolymer Random - Repeat Pattern = Head to Tail (default)

19) ChemDraw 18 - Bracket Usage = Copolymer Random - Repeat Pattern = Head to Head

20) ChemDraw 18 - Bracket Usage = Copolymer Random - Repeat Pattern = Either/Unknown

21) ChemDraw 18 - Bracket Usage = Crosslink - Repeat Pattern = Head to Tail (default)

22) ChemDraw 18 - Bracket Usage = Crosslink - Repeat Pattern = Head to Head

23) ChemDraw 18 - Bracket Usage = Crosslink - Repeat Pattern = Either/Unknown

24) ChemDraw 18 - Bracket Usage = Generic - Repeat Pattern = Head to Tail (default)

25) ChemDraw 18 - Bracket Usage = Generic - Repeat Pattern = Head to Head

26) ChemDraw 18 - Bracket Usage = Generic - Repeat Pattern = Either/Unknown

27) ChemDraw 18 - Bracket Usage = Graft - Repeat Pattern = Head to Tail (default)

28) ChemDraw 18 - Bracket Usage = Graft - Repeat Pattern = Head to Head

29) ChemDraw 18 - Bracket Usage = Graft - Repeat Pattern = Either/Unknown

30) ChemDraw 18 - Bracket Usage = Modification - Repeat Pattern = Head to Tail (default)

31) ChemDraw 18 - Bracket Usage = Modification - Repeat Pattern = Head to Head

32) ChemDraw 18 - Bracket Usage = Modification - Repeat Pattern = Either/Unknown

Other bracket notations may be available in ChemDraw that has not be tested and could result in even more duplicate molecules. 

 

For registration of mixtures (multi-compound) structures, please visit these articles

https://support.collaborativedrug.com/hc/en-us/articles/360001024943-Single-Registration-of-Chemical-Entities

https://support.collaborativedrug.com/hc/en-us/articles/214358223-Is-it-possible-to-add-structures-to-structureless-molecules-#3