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I am trying to create a KNIME workflow that would accept a list of compounds and carry out bioisosteric replacements (we will use the following example here: carboxylic acid to tetrazole) automatically.

NOTE: I am using the following workflow as inspiration : RDKit-bioisosteres (myexperiment.org). This uses a text file as SMARTS input. I cannot seem to replicate the SMARTS format used here.

For this, I plan to use the Rdkit One Component Reaction node which uses a set of compounds to carry out the reaction on as input and a SMARTS string that defines the reaction.

My issue is the generation of a working SMARTS string describing the reaction.

I would like to input two SDF files (or another format, not particularly attached to SDF): one with the group to replace (carboxylic acid) and one with the list of possible bioisosteric replacements (tetrazole). I would then combine these two in KNIME and generate a SMARTS string for the reaction to then be used in the Rdkit One Component Reaction node.

NOTE: The input SDF files have the structures written with an attachment point (*COOH for the carboxylic acid for example) which defines where the group to replace is attached. I suspect this is the cause of many of the issues I am experiencing.

So far, I can easily generate the reactions in RXN format using the Reaction Builder node from the Indigo node package. However, converting this reaction into a SMARTS string that is accepted by the Rdkit One Component Reaction node has proven tricky.

What I have tried so far:

  1. Converting RXN to SMARTS (Molecule Type Cast node) : gives the following error code : scanner: BufferScanner::read() error

  2. Converting the Source and Target molecules into SMARTS (Molecule Type Cast node) : gives the following error code : SMILES loader: unrecognised lowercase symbol: y

    • showing this as a string in KNIME shows that the conversion is not carried out and the string is of SDF format : *filename*.sdf 0 0 0 0 0 0 0 V3000M V30 BEGIN etc.
  3. Converting the Source and Target molecules into RDkit first (RDkit from Molecule node) then from RDkit into SMARTS (RDkit to Molecule node, SMARTS option). This outputs the following SMARTS strings:

    • Carboxylic acid : [#6](-[#8])=[#8]
    • Tetrazole : [#6]1:[#7H]:[#7]:[#7]:[#7]:1

This is as close as I've managed to get. I can then join these two smarts strings with >> in between (output: [#6](-[#8])=[#8]>>[#6]1:[#7H]:[#7]:[#7]:[#7]:1) to create a SMARTS reaction string but this is not accepted as an input for the Rdkit One Component Reaction node.

Error message in KNIME console : ERROR RDKit One Component Reaction 0:40 Creation of Reaction from SMARTS value failed: null WARN RDKit One Component Reaction 0:40 Invalid Reaction SMARTS: missing

Note that the SMARTS strings that this last option (3.) generates are very different than the ones used in the myexperiments.org example ([*:1][C:2]([OH])=O>>[*:1][C:2]1=NNN=N1). I also seem to have lost the attachment point information through these conversions which are likely to cause issues in the rest of the workflow.

Therefore I am looking for a way to generate the SMARTS strings used in the myexperiments.org example on my own sets of substituents. Obviously doing this by hand is not an option. I would also like this workflow to use only the open-source nodes available in KNIME and not proprietary nodes (Schrodinger etc.).

Hopefully, someone can help me out with this. If you need my current workflow I am happy to upload that with the source files if required.

Thanks in advance for your help,

Stay safe and healthy!

-Antoine

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  • $\begingroup$ +100. Great first question! Welcome to the community and thank you for contributing your question here! We hope to see much more of you !!! $\endgroup$ – Nike Dattani Oct 14 '20 at 11:23
  • $\begingroup$ It's a good question but can you upload the input files too. It would be helpful tp people who intend to answer it $\endgroup$ – Anoop A Nair Oct 14 '20 at 17:11
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    $\begingroup$ Yes please do upload the input files and all relevant data files! The guideline is that if it's a few hundred lines, copy and paste it into a "code block", otherwise upload it to our GitHub page: github.com/HPQC-LABS/Modeling_Matters (make a folder called 3499, since as you can see from the URL, this question is post #3499 on this site). $\endgroup$ – Nike Dattani Oct 16 '20 at 0:02
  • $\begingroup$ Hi Antoine, are you able to upload the input files? $\endgroup$ – Nike Dattani Nov 27 '20 at 21:53