Open-Source Coronavirus Monthly Update Meeting #9: 17:00-18:00 BST, Monday 13th February 2023.

[TomkUCL]

Date: Monday 13th February 2023. Time: 5pm GMT (other times) Place: https://ucl.zoom.us/j/97172937586 Recording: https://youtu.be/v2wHMMvlH-A

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: @TomkUCL @mattodd @tmw20653 @SumeraMalik123 @KangpingL @ahsgc, Peter brown (UoT), @kipUNC, Alex Tropsha (UNC), @jamesday100, @StructuralGenomicsConsortium/cnp4-nsp13

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.

https://github.com/orgs/StructuralGenomicsConsortium/teams/cnp4-nsp13 rough agenda:

Agenda:

Status of the SPR and ATPase Assay: Getting up and running #25 @SumeraMalik123 @ahsgc to discuss SPR assay, including regeneration conditions of the protein from the positive control (PUG) as well as new data from compounds screened;

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.

@TomkUCL @KangpingL - Synthesis of mono-Boc protected diamine linkers for the synthesis of Kostya's generative library set - in most cases the end units are already available.

Note - successful creation of these novel building blocks will allow the enumeration of large virtual libraries that we could involve in screening vs other targets.

As requested by @tmw20653, @kipUNC to outline a paper that will describe the origin of these compounds.

Next Meeting: Mon March 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]

@ahsgc forwarded the three N-oxide hits that have shown promise. The following text is now included in the Story So Far page:

In early 2023, three hits (below) were identified with sufficient promise that a dedicated chemical synthesis campaign was initiated to explore them. It is not yet clear that they are binding to the site relevant to this project.

[mattodd]

Comment from Rahman Saleem (from LUMS, Pakistan), who kindly emailed after watching the meeting recording. Recommended looking at aldisin as a means to explore benzoazepine SAR with simple chemistry. @TomkUCL @ahsgc

[AndyXGH]

I docked the three N-oxide molecules into C-terminus-B pocket (column: -42.6392/ 32.4983/ -4.49593, size: 16/ 16/ 16) using Vina, their respective Vina scores are:

RA0001264-01: -5.6 kcal/mol RA0001283-01: -5.4 kcal/mol RA0001263-01: -6.2 kcal/mol

Apart from 1263, the other two aren't much improved binders than the three fragments reported by Newman (5RM3, 6, 9, Vina score ≈ -5.2 kcal/mol).

Will look into their respective binding mode and post here.

[TomkUCL]

@AndyXGH this is typical of the N-oxide series - typically Vina scores don't show much improvement in terms of binding affinity as compared to the fragments however they tend to form more interactions. I think it is worth @kipUNC docking the original fragments in GLIDE so that we have both GLIDE and VINA scores as benchmarks for the original fragments (shown below for reference).