Open-Source Coronavirus Monthly Update Meeting #8: 17:00-18:00 BST, Monday 9th January 2023.

[TomkUCL]

Date: Monday 9th January 2023. Time: 5pm GMT (other times) Place: https://ucl.zoom.us/j/97172937586 Recording:

• [ ] @TomkUCL to upload recording to YouTube from the Zoom recording as per the instructions, then delete this text.

Previous Meeting: issue https://github.com/StructuralGenomicsConsortium/CNP4-Nsp13-C-terminus-B/issues/31 Who can come?: Anyone. No need to say anything unless you'd like to. If you'd like to contribute, please join Github.

Attending:

Slide decks: Please https://github.com/orgs/StructuralGenomicsConsortium/teams/cnp4-nsp13 remember that if you share slides/info, drag and drop those into a comment on this page, below. Very easy and saves @mattodd having to pester you.

@StructuralGenomicsConsortium/cnp4-nsp13 rough agenda:

Agenda: 1) Status and planning for the SPR assay https://github.com/StructuralGenomicsConsortium/CNP4-Nsp13-C-terminus-B/issues/25 @SumeraMalik123 to discuss SPR assay, including regeneration conditions of the protein from the positive control (PUG). Also any new data from compounds screened.

2) Synthesis and Molecule Procurement: Where we are up to with the set of molecules predicted by Kostya to be binders - the comparison between the Enamine docking set and the generative set. @ahsgc - delivery of 9.50g of a key common intermediate from Pyramal for Generative set compounds (SMILES string: O=C(O)CC1=CC=C(F)C=N1). @TomkUCL - what's already come in, what's coming in, what's scheduled, and whether any molecules are currently not scheduled for delivery (and might need replacing).

Next Meeting: Mon Feb 13th 5pm UK time at https://ucl.zoom.us/j/97172937586

L'esprit de l'escalier If you'd like to follow up after the meeting, please comment below. You can also email, but please be clear if anything in the email should not be public domain - the default is open.

[mattodd]

Anwar's slides have been uploaded to the File Diary, and are here:

20230109 AViDD NSP13 Inhibitors Updates Anwar.pptx

Campaign 05 - are these the same as the ones @TomkUCL is looking at, @ahsgc ?

• [x] @TomkUCL to set up meeting with @ahsgc and @kipUNC ASAP to discuss how to apply generative approaches to the linking core of predicted structures while keeping pendant groups constant.

@jamesday100 asked whether, based on the experimental data to date, we have any matched pairs that tell us anything about what motifs (e.g., N-oxide) are important. Answer from @toluene44: not yet, but some structures coming.

[TomkUCL]

Tom's meeting slides: Presentation 1.pdf

A summary of the compounds to be synthesized can be seen here - arranged by most negative (top left) to positive (bottom right) GLIDE score. @ahsgc for discussion in today's 1-to-1.

Enamine REAL list compounds to be made:

De-novo generative list compounds to be made: N-OH is the N-oxide in these structures, i.e. N+O-

[TomkUCL]

Now that have both acids (pyridine N-oxide and 5-fluoropyridine acetic acid) readily available on a multigram scale, @ahsgc and I agreed to prioritise these diamine linkers based on chemical variation (rather than GLIDE score) to maximise coverage of the chemical space, simplify chemistry and maximise synthesis output. This means that chemistry can be narrowed down massively to synthesis of non-commercial diamines and simple amide couplings.

The list of amine linkers below is from the series above by excluding N-oxide and 5-fluoropyridine acetic acid motifs. The list was generated by breaking amide bonds on either side of the common motifs mentioned above.

Linkers are classified into four generative (G) classes; simple aliphatic diamines (G1), aromatic diamines (G2), one common motif substituted (G3), and both common motifs substituted (G4). abs = absolute stereochemistry, & = racemic mixture.

[ahsgc]

Campaign 05 - are these the same as the ones @TomkUCL is looking at, @ahsgc ?

Hi @mattodd here are our paths:

1. Tom is working on non-purchasable Enamine REAL Hits
2. We are working on Generative Hits

But as a template wise we have common building blocks!

[ahsgc]

Now that have both acids (pyridine N-oxide and 5-fluoropyridine acetic acid) readily available on a multigram scale, @ahsgc and I agreed to prioritise these diamine linkers based on chemical variation (rather than GLIDE score) to maximise coverage of the chemical space, simplify chemistry and maximise synthesis output. This means that chemistry can be narrowed down massively to synthesis of non-commercial diamines and simple amide couplings.

The list of amine linkers below is from the series above by excluding N-oxide and 5-fluoropyridine acetic acid motifs. The list was generated by breaking amide bonds on either side of the common motifs mentioned above.

Linkers are classified into four generative (G) classes; simple aliphatic diamines (G1), aromatic diamines (G2), one common motif substituted (G3), and both common motifs substituted (G4). abs = absolute stereochemistry, & = racemic mixture.

Hi @TomkUCL, it is a good and workable start!

Here are a few steps to follow:

1. Narrow this list of building blocks to those that are purchasable (~also pay attention to which are not crazy expensive)
2. Purchase other available and close diamine building blocks
3. After confirming this list, send the list of intended compounds to @kipUNC for a quick docking
4. Please make the compound as simple and faster way as possible.
5. After any moderate hits or potential chemotype, we can deep dive for SAR

This list is not for SAR; it is just to test the hypothesis and develop our confidence that the model is working. So, we need as many representative compounds as possible.

@TomkUCL can you do this more transferable and accessible, like:

1. When you share the structures, share the chemdraw or SMILES so anyone can cross-check, design, re-design analogs, etc., instead of going back and forth
2. If you upload any slides (or present), please make the structures big enough to read clearly

Cheers!

[mattodd]

Hi @TomkUCL - do you know where the recording is for this meeting? I don't have it on my Zoom list and it's not yet at https://www.youtube.com/playlist?list=PL0eLxnHhou_k8BLh9IBYONsRwRcgtVykq I don't think.