Antiviral assay data for Catalogue and ASAP compounds

[HadiaAmahli]

Antiviral profiling of these compounds 25 catalogue compounds and 10 ASAP toolbox compounds was done in collaborating lab by Marcia Kay Sanders. The data is available in the files below:
EXP0200 - Part 1.zip
EXP0200 - Part 2.zip

Among the ASAP toolbox compounds, one compound was mentioned as 13uM inhibitor, however, most of the curves were not meaningful.

The catalogue compounds, on the other hand, yielded some good-looking curves with decent cytotoxicity profile. For example:



compared to standard

Considering the compounds are still in the fragment range, the curves are incomplete even at the highest tested concentration of 40uM. For a comparison of the antiviral activity of the compounds at 40uM, here is a graphic with compounds arranged in a manner reflective of structure similarity:

The most important message from the figure above was that we were able to see the antiviral activity in the compounds that were identified in the soaking experiment. We now plan to test these compounds through Isothermal Titration Calorimetry as another orthogonal assay to determine the dissociation constant, KD.

[HadiaAmahli]

@tmw20653 @ahsgc @rahmanszsaleem Based on the GCI and the crystallography data we received so far, we nominated three hits (see below) to study their SAR and proceed with their expansion.

We discussed the priority of our chemistry starting point regarding this data and decided to prioritise the top rated hit: RA-0188454-02

showed Kd~4 µM, see here

[jasminaschenbrenner]

Hi @HadiaAmahli, @rahmanszsaleem,
can you please reiterate the reasons that it was decided to prioritise RA-0188454-02? Comparing it to the other two hits, I remember that RA-0188454-02 was more 'risky' as it forms mainly water bridges with the protein instead of direct interactions, so it sits not directly in the pocket, and it actually does not bind at all in a way it was predicted to, based on the fragments it originated from.
Just so that we can follow the thought process.

[mattodd]

@jasminaschenbrenner yes indeed, but the orthogonal GCI assay showed a better curve than the other two, sadly. The other two compounds are also to be pursued, and can be accessed using the same chemistry.

(@HadiaAmahli can you add pictures to the actual issue (rather than as links) just by dragging them onto the Issue? That way we can see everything together.

The slide I presented at the f2f meeting is this onem below. Does this still accurately reflect the state of play with respect to there being boxes around the compounds that gave good GCI curves?

Talking with Wenjie today, I think that compound Z9101663889, which gave a Jasmin Top Rating, has not yet been tested by GCI. We will need to fix that ASAP.

[HadiaAmahli]

@mattodd I arranged this table as an answer to your question above and which explains the status of the compounds highlighted in green.

Due to the old samples consumption, new batch of the compounds has been purchased to enable @Wenjie-Ch to run GCI experiment and to repeat the experiment for some compounds that showed confusing data comparing with the crystallography data:
e.i: Z86430593 which is the top rated compound based on the crystal structure data, it showed no binding on the GCI data!