OSA Meeting Friday November 27th 2020

[mattodd]

The following is draft until this text is deleted.

Meeting Nov 27th 2020 at 2pm UK time at https://ucl.zoom.us/j/92800004715. This page follows on from #41 .

Recording is here.

On the call:

1. Screening.
   a) New compound suggestions: New compounds were proposed last time (OSA Meeting Friday November 6th 2020 #38). Main branch: exploration of the para-methyl substituted compound that was active. meta-subst compounds were inactive, but this should be explored e.g. Topliss movement of chlorine/methyl around the ring. @drc007 reminded us to keep an eye on logP. Top five (LHS of slide in OSA Meeting Friday November 6th 2020 #38) higher priority than the lower three.

Suzuki couplings are being pursued by @edwintse

RHS panel of slide in #38: exploration of amine pendants on both original and DNDi cores.

Also: playing with the imidazole and pyridine heteroatoms, re the possibility of the chelation mechanism by the bidentate ligand. e.g. thiazole bioisostere replacement of pyridine. Proposed pyrrole compound would be N-H donor, not chelator, which would be interesting. Also suggestion by @MFernflower in #42
@edwintse generally to keep an eye on synthetic accessibility/SM's.
Methoxy on the red core is proposed as a result of an existing matched pair spotted by @danaklug.
@mattodd reminded people to keep an eye on lit searches in case of any scaffold hops as we change things more.
@loriferrins has suggested compounds she can send in here: N-alkylated compounds. 7-sub'd core seems to be more toxic to human cells (less toxic with 6-sub'd <-- observation by NEU @loriferrins) Action on @loriferrins to ship to UCL.
Q: @drc007 suggested related compounds may have already been made by DNDi - @danaklug to reach out to @bendndi
Discussion to continue on #35.

@loriferrins also has other data (e.g. tox) on these cores, and is actively exploring them, so we can exchange structures.

b) Human Cytotox: Happening in the lab of Andreas Schatzlein. This is also to test the metal-binding potential of the 2-pyridyl system. More information at issue #3 .

2. Synthetic Chemistry Update by @edwintse and @danaklug . See below for slide.

3. in vitro PK:
   a) Residual uncertainty about the units between original data and those from Monash. Resolved in OSA Meeting Friday November 20th 2020 #41 !

b) Benzofuran compound (821) will be evaluated for metabolic ID by Hypha (paperwork complete!).

4. Community updates
   a) Videos: One-minute video update using the Tha/Dana protocol (How Can We Democratize Making 30-second Captioned Videos for Updates? OpenSourceMalaria/TechOps#3) has been done! Action on @danaklug to add captions and then post, then see how well it functions on social media. @mattodd's view is that the videos should focus on short, specific things, but this video is an excellent start.

b) Newsletters. Another one needed, on Series 1 this time. People need to give their consent to be emailed, and we need a record of that. Action on @danaklug to set up Google Form for sign-up, to solve GDPR issue.

5. Molecule contributions
   @drc007 suggested we try to crowdsource physical compounds - how? Twitter? Email? Newsletter? Would be helpful create landing page for molecule contributions (likely through GitHub). @danaklug has created a submission template now available at Sample Contributions #39. Action on @mattodd to investigate adopting licence terms from SGC's compound submission system.
   @drc007 said he was happy to reach out to people in his professional network to see if any related compounds are held and may be donated (Action)
   @mattodd mentioned the value of having a Twitter Bot that takes a molecule from the OSA spreadsheet and tweets out the structure with the strings and with a page where it is clear what the use of the molecule is. This allows for human to spot the molecules that OSA requires.
   @mattodd also reminded people to keep an eye on sites such as Enamine, Manifold and Mcule, to check whether any molecules might be commercially available. We should always try to make the challenging molecules in the lab, and buy the others.

AOB:

6. Mechanism of action: Experiments ongoing (see OSA Meeting Friday Oct 2nd 2020 #30); update received, results expected soon.

7. Biofunctionalisation: Action Contract signed with Hypha, compound shipped. Details:

8. Series Origin/Similarity Landscape: Mat is awaiting clearance for the GSK conversation and will report back when that's received. GSK are aware and are pursuing clearance.

9. 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 yesterday). 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).

Actions other than the chemical targets discussed (can be checked as complete after the meeting).

• ACTION ITEM: Lori to ship some compounds to UCL for MRSA eval
• ACTION ITEM: Lori to dig up relevant tox data on these compounds
• ACTION ITEM: Mat to report back on Hypha.
• ACTION ITEM: Mat to report back from GSK on what can be shared publicly about the series history.
• ACTION ITEM: Dana or Ed to try out the Labarchives drawing facility.
• ACTION ITEM: Chris to look into why the OSA molecule sheet is not Google-indexed.
• ACTION ITEM: Mat to look into license terms for compound donation
• ACTION ITEM: Chris to reach out to professional network for compound donations
• ACTION ITEM: This meeting video to be posted on YouTube.

[edwintse]

[danaklug]

I've tracked down the ADME data for the NEU compounds and uploaded it here. Will try to integrate the data into the master spreadsheet in the near future and will chase the tox data for this shipment and the next one from @loriferrins.

[danaklug]

The N-benzyl compound that @drc007 and I were remembering is OSA_000842, MRSA MIC = 8 and VRE MIC = 32 ug/mL. Adding this compound with the unsubstituted DNDI core to the list.

[drc007]

One of the nice features of the COVID moonshot proposals is they ask that suggestions are accompanied by a rational, what is the question that will be addressed by a compound, or why it should be made. I can see it being useful later for compiling the story behind compounds and eventual publications.

[MFernflower]

Sorry about all the github posting - I had made a mistake on my compound list!

Here is the final compounds I proposed this meeting:

@danaklug @edwintse @mattodd

They are quite oily but they are needed to fill SAR holes

[MFernflower]

@drc007 I indeed cannot wait until we get a proper molecule management system!

[danaklug]

Closing - the issue has been linked in the Project Meetings wiki.