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opensourceantibiotics / Series-2-Diarylimidazoles

Open Source Antibiotics Series 2
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OSA Series 2 Meeting Nov 19th (No meeting Nov 12th) #102

Closed mattodd closed 2 years ago

mattodd commented 3 years ago

This page is draft until this text is removed.

Meeting Nov 5th 2021 at 2pm UK time at https://ucl.zoom.us/j/92800004715. Follows on from #100

Recording:

On the call:

  1. Discussion of which compounds to ship to NEU for ADME data
    • There are 12 slots available (LogD, PPB, HLM Clint, rat hepatocyte Clint, aq. sol.)
    • @danaklug Analysis below
    • @edwintse Clustering?
  2. AOB
    • @QSimpson N-alkylated compunds
    • Any updates from Lee/Alex?

PREVIOUS ACTIONS

drc007 commented 3 years ago

Ok with me

Chris

On 11 Nov 2021, at 23:38, Mat Todd @.***> wrote:

Draft till this text removed

Let's postpone the Nov 12th meeting till Nov 19th. Hopefully OK @drc007 https://github.com/drc007 @flavioemery https://github.com/flavioemery @danaklug https://github.com/danaklug @edwintse https://github.com/edwintse @loriferrins https://github.com/loriferrins @QSimpson https://github.com/QSimpson @MFernflower https://github.com/MFernflower @danielgedder https://github.com/danielgedder - not gotten round to posting recording of last meeting and digesting points.

Actions remain as per #100 https://github.com/opensourceantibiotics/Series-2-Diarylimidazoles/issues/100 (still need discussion of which compounds to ship to NEU for ADME data) and I will chase Lee Graves re MoA. Alex is chasing doing DNA interaction experiments.

Agenda etc for Nov 19th can be posted here.

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danaklug commented 3 years ago

Food for thought re: NEU ADME assays.

I thought it might be useful to look at potential candidates in the context of their matched pairs, hopefully this is helpful. Compounds in dotted boxes are ones that we should have stock of at UCL (to be confirmed) and that we don't have any ADME data on yet.

ADME_11-11-21

Note that we have ADME data for some additional compounds, but I've based this selection on what's included in the current SAR tables. There are also a few compounds from NEU for which we don't have ADME - for these I've asked @loriferrins if she has this data and can share. I have not included any compounds from @danielgedder or ones that were donated from DNDi as potential candidates because we don’t have solid stock of them at UCL. However we could consider trying to source more of those if we think it’s important to get ADME data on them.

For me, the four top priority compounds are: • OSA_1018: Bridging compound that appears on multiple SAR tables • OSA_987: Bridging compound that appears on multiple SAR tables • OSA_975: Compare to OSA_864. Retains the –CN group that appears to result in improved ADME, but is equipotent to OSA_821 and OSA_865. If this compound has a good ADME profile, it could be a frontrunner of the series. • OSA_821: Would provide a nice bridge between Monash and NEU ADME data.

Other compounds potentially of interest: • OSA_1011: Is potent and contains a basic amine • OSA_988: Completes NH linker table

At this point, my opinion is that it’s not really worth sending anything for ADME with MRSA MIC >4. Happy to have this up for discussion though as we do have room to include some of these with the priority ones.

lferrins commented 3 years ago

@danaklug this is a really helpful summary, as always! I completely agree with your analysis - you could include 875 if you wanted to (purely based on potency), though I don't anticipate it will be any better/different than 876. I also agree that there isn't a lot of value in getting data on compounds that are >4ug/mL.

I have also emailed the missing ADME data to Dana as this came in earlier in the week.

danaklug commented 3 years ago

Thanks Lori, new data has been added to the master sheet and uploaded.

edwintse commented 3 years ago

Cluster analysis of the Series 2 compounds

Screenshot 2021-11-19 at 12 06 26 pm

OSA S2 Similarity.dwar.zip

mattodd commented 3 years ago

So, confirming choices 875 for sure. 1018 for sure 987 yes 821 control 1011 988 875 maybe as comparison with 876

Actions Ed to deploy Datawarrior jedi skills to annotate the fig above to check that these choices are diverse and fill gaps. Though honestly we're pretty well covered on the compounds already! Mat or Dana to check with Paul S about the next eval round Quillon to ship new compounds (awesome) though it is holiday season... Mat to catch up with Lee re MoA Dana to catch up with Alex re DNA binding experiments (talking to Gary P already).

Nice to see you on camera @MFernflower - first time I think!

MFernflower commented 3 years ago

@mattodd @QSimpson said there is a new postdoc - maybe if they have time they could make these two compounds???

image

danielgedder commented 2 years ago

Closing: data incorporated into wiki: https://github.com/opensourceantibiotics/Series-2-Diarylimidazoles/wiki/Metabolic-Clearance-Data