OSA Meeting Friday March 26th 2021

[mattodd]

Draft till this text removed.

Meeting March 26th 2021 at 2pm UK time at https://ucl.zoom.us/j/92800004715. This page follows on from #61.

Recording is [here].

On the call:

1. Screening

a) Potency

• New compounds incoming from @loriferrins #62. These usefully explore the electronics of the pyridine ring, which will influence chelation ability. Do we need to set up MRSA evaluation?

• @flavioemery couldn't make the last meeting but will check the master list to see if there's anything of interest we can share with him.

• @loriferrins shared structures that are available for N-alkylation in #63. Which should we prioritise? Based on the available potency data @mattodd suggests compounds related to OSA979 and OSA983, i.e. simple branched alkyl on the aniline N, so:

Analogous compounds that make sense: NEU-0006492 simple halo subst. NEU-0006462 ditto NEU-0006459 ditto

We've not had a lot of luck with OMe on the fused aromatic ring (e.g. OSA980, OSA851, OSA839). We've not explored other substituents there, so potentially these:

NEU-0006495 NEU-0006487 NEU-0006815 NEU-0006816 NEU-0006494

Picture = 1000 words:

b) Parallel DNDI assay We're sending some compounds to @loriferrins for insertion into DNDi's panel for potency eval vs Leish/Chagas. Compounds to send...? @danaklug posted the compounds for which we have decent stocks to #60. Looks like we ship the lot? Next steps here?

c) Human Cytotox Compounds OSA979-984 have been delivered to Alex and Ireno for tox eval. This is currently the most crucial experiment. Any updates on potential timescale @danaklug ?

2. Synthetic Chemistry (We may be a bit light on this - we're waiting on tox eval and there are other high priority commitments outside this series in the short term)

3. in vitro PK @danaklug to post Hypha analytical traces in advance of an experimental purification of the major metabolite.

Can we remove --> Solubility data. Lori presented data in #56 on OSA979-984. Do we have these data anywhere?

4. Community updates a) Newsletters. Third newsletter being written. Focus on this series.

5. Mechanism of Action Waiting to see if OSA983 is a better molecule for follow-up experiments before contacting Lee Graves and team.

6. ELN @danaklug or @edwintse to try again (Action) Labarchives' molecule sketching facility to see if the ELN page is Google-able. i.e. sketch a molecule from OSA using the drawing facility, and check each day to see if it is indexed. ELN pages on which strings have been manually pasted are indexed (@mattodd checked this). Can we do away with manual strings pasting? Separately, @mattodd found that the OSA molecule spreadsheet is not indexed. @drc007 said he would check this out (Action). <-- @drc007 can we remove this, or are further actions needed?

AOB

• Guest appearance today by Isabelle Giraud who will describe how to auto-import the OSA Master List into Datawarrior.

• Can we start to assemble paper on this series in order to summarize SAR learnings?

• Last week @mc-robinson showed Manifold as a way for us to keep an eye on purchaseable space. Action on @edwintse to include this in wiki somewhere logical. Action on @MFernflower to sign up (will need to ask Matt R for access) and to try a search on the aniline cores around OSA983

• Any other places that @Giada-chem should be looking for clues as to MoA/target?

Actions

• [ ] @danaklug to look into whether manual strings are still needed in Labarchives, or whether molecule sketching facility is sufficient.
• [ ] New potency evaluations for the incoming NEU compounds?
• [ ] @danaklug chase Alex for tox evaluation timetable.
• [ ] @danaklug ship compounds for DNDi Chagas assay
• [ ] @edwintse to install reference to e.g. Manifold (and other resources) on wiki.
• [ ] @MFernflower to use Manifold to highlight commercially available chemical space near OSA983.
• [ ] @drc007 to look into why the OSA molecule sheet is not Google-indexed.
• [ ] @danaklug to post Hypha analytical traces in advance of an experimental purification of the major metabolite
• [ ] @mattodd to write and send next OSA newsletter
• [ ] This meeting to be posted on YouTube.

[lferrins]

Attaching the ChemDraw for the compounds for N-alkylation prioritisation. Sorry about the zipped folder, turns out GitHub doesn't support ChemDraw files!

OSA.zip

[mattodd]

I know, it's a pain. Thanks for the file. I have 10 minutes with nothing going on (a.k.a "heaven") and so will play with it.

Done. My own chemdraw's here, with the pic above OSA_Compounds_for_alkylation Shortlisted.zip

[MFernflower]

@mc-robinson i send an email RE manifold account

hopefully you got it

[mc-robinson]

@MFernflower, got it thanks, best way forward is likely for you to create an account here https://postera.ai/sign-up?redirectTo=/manifold and click "apply for an academic license." I'll make sure our team approves it on the backend.

[danaklug]

I've just heard from Alex - she said she's got a lot on at the moment but hopes to have some data for us next week. I'll post any updates I get at #3.