RDKit Two Component Reaction, chirality of building block not retained.

KNIME Extensions
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1

Hello all,

I am trying to enumerate a virtual library using the RDKit Two Component Reaction node in Knime.
The enumeration is based on an amide coupling of a chiral amine and different acidic building blocks.
Although the chirality of some building blocks is defined, I am unable to retain this information in the enumerated products. Interestingly, the chirality of the amine is retained.

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I am using Knime 5.3.3 installed automatically with the Maestro (Schrodinger).

Can you please advise?

Many thanks in advance,
Kind regards,
Silvia

Example of workflow

Enumeration_WF.knwf (19.1 KB)

Example of acidic BBs

CC(C)(C)OC(=O)N1CC@HC(=O)O
CC(=O)NC@@HC(=O)O

Amine: NC@HC1=CC=CC=C1

2

@sb123 Welcome to the forum!

It looks like the SMILES files are stored on your local system and are not included in the shared workflow. Could you please attach the files to the workflow data area and reference them using workflow-relative paths?
Check the KNIME docs on workflow-relative paths here:

1 Like
3

Hi @k10shetty1 ,
Thanks for your reply.
Some examples of SMILES of the acidic building blocks are at the bottom of my initial message. The “amine.sdf” file is pasted below.
I believe that with the information provided you should be able to run the workflow I initially shared.

Kind regards,
Silvia

amine.sdf
ChemDraw01142616032D

0 0 0 0 0 0 V3000
M V30 BEGIN CTAB
M V30 COUNTS 9 9 0 0 1
M V30 BEGIN ATOM
M V30 1 C -1.428942 -0.000000 0.000000 0
M V30 2 C -1.428942 -0.825000 0.000000 0
M V30 3 C -0.714471 -1.237500 0.000000 0
M V30 4 C -0.000000 -0.825000 0.000000 0
M V30 5 C -0.000000 -0.000000 0.000000 0
M V30 6 C -0.714471 0.412500 0.000000 0
M V30 7 C 0.714471 0.412500 0.000000 0
M V30 8 N 1.428942 0.000000 0.000000 0
M V30 9 C 0.714471 1.237500 0.000000 0
M V30 END ATOM
M V30 BEGIN BOND
M V30 1 2 1 2
M V30 2 1 2 3
M V30 3 2 3 4
M V30 4 1 4 5
M V30 5 2 5 6
M V30 6 1 6 1
M V30 7 1 5 7
M V30 8 1 7 8
M V30 9 1 7 9 CFG=1
M V30 END BOND
M V30 END CTAB
M END
$$$$

4

I tested this by entering the following SMILES in a Table Creator, and the chirality was retained in the products (see screenshot below).

  • Amine: C[C@@H](N)c1ccccc1
  • Reactant 2 : CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
  • Reactant 2 : CC(C)(C)OC(=O)N1C[C@H](C2=CC=CC=C2Cl)[C@@H](C1)C(=O)O

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image1951Ă—577 70.5 KB

Since this differs from what you’re seeing, the issue is likely related to how the SDF/SMILES are imported. Could you please share your workflow (.knwf) and a small sample of the input files you use for the acidic BBs and amine? That would be helpful to check the node configuration and any sanitization settings in detail.

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5

Thanks for the help @k10shetty1.
In my case, I was not able to see a “sensible” 2D structure for the enumerated products, when looking at the output of the reaction enumeration node (see green column from the screenshot below). Calculating the canonical SMILES of the products has fixed the issue and the stereochemistry of both building blocks is retained (yellow columns).

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image1291Ă—362 41 KB

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