Finalizing paper, MetID and MMV669848

[mattodd]

While finalising the nature of Sue Charman's contribution I noticed that we are not currently mentioning the metID work that was done originally (report is here) and that we do not in the paper mention MMV669848.

1) I think we should at least mention the metID work, even though it did not dramatically alter the nature of what we were doing (we didn't ever drill down further). e.g. a sentence in the paper and making sure that the Monash report is in the SI.

2) Is MMV669848 left out intentionally, does anyone know? No problem, just wanting to make sure this has been asked/answered.

Tagging @MedChemProf @edwintse @danaklug @drc007 in case anyone has thoughts on this briefly.

[MedChemProf]

@mattodd I apologize for the delayed response. I just had a chance to look at the paper again, focusing on the sections that would be impacted by the questions you raised above. In terms of MMV669848, I at first thought that maybe it was lost during one of the revisions, so I started looking back at older versions back to January of 2020 and could not find it. So for some reason it slipped through the cracks. There is actually room to add it back in in Table 3 on page 8 of the manuscript. A sentence would have to be added to the discussion section on page 7 noting the compounds potency (0.11 uM) and that it just was not followed up on. In terms of the metabolic study, I think there may have just been an assumption that the late-stage biofunctionalization study covered the topic. I re-read the metabolite id paper that you referenced and I think it could be mentioned that the results in that study largely confirm the metabolic hotspots on the series (triazolopyrazine, benzylic carbon). It should be mentioned, but I think it can be added to the SI.

Also, I did notice on page 7 of the paper in the second to past paragraph that the the amine OSM-S-368 is mentioned in reference to its structure in Table 3. I think that was a transposition typo, and the structure should say amine OSM-S-638.

Finally, thanks for having me take another look at the manuscript. While looking it over again I was impressed by the improvements to the tables and figures as compared to our earlier google docs version. Very nice job @edwintse and @danaklug .

[cdsouthan]

MMV669848 = https://pubchem.ncbi.nlm.nih.gov/compound/76333084

Slightly odd that MMV669848 as name did not come through to the CID from the 2014 OSM ChEMBL submission, but hey...

https://www.ebi.ac.uk/chembl/g/#browse/activities/filter/molecule_chembl_id%3A(%22CHEMBL3137616%22)%20AND%20standard_type%3A(%22EC50%22)

Last of the ducks to line up? @MedChemProf Cheers to all

[MedChemProf]

I just uploaded to the preprint folder a new spreadsheet with MMV669848 / OSM-S-380 included. I also uploaded the Charman Metabolite study for inclusion in the SI.

[MedChemProf]

All, I just uploaded the spreadsheets again to the preprint upload server repository. I added a column that was requested for the activity in 2 significant figures. I also found a few more errors that have been corrected. I uploaded an excel and csv version.

I also found a few more minor edits in the manuscript that I could not change. In Figure 5 on page 10, suggest changing IDs OSM-W-9 and OSM-W-5 in figure to OSM-W-009 and OSM-W-005 for consistency.

[cdsouthan]

Are we going for Chemrxiv for the preprint @mattodd @MedChemProf ? Its pretty good, (got a few on their already :)

https://chemrxiv.org/engage/chemrxiv/search-dashboard?text=Christopher%20Southan

[cdsouthan]

Not exactly a rush but if we get the preprint out with a doi soon-ish it might get cited in an antimalarial review that, as of June 2022 is now in review for the British Journal of Pharmacology

[MedChemProf]

All, just as a follow-up, I would be happy to chip-in to try and get over any last hurdles for either the preprint upload or journal submission. Please let me know the status and happy to help. Thanks.

[MFernflower]

@mattodd I've not been following this for a long time - what is the current progress of the paper?

[mattodd]

Hi all,

While considering the above question of compound MMV669848 (OSM-S-380) I realised that we have no hepatocyte data in the paper. I looked into this further and according to the Master List we have some such data for 11 compounds. Here is a draft figure that is not complete.

(Chemdraw below if people want to adapt/add).

i.e. the compounds are these:

218, MMV669844 272, MMV639565 353, MMV693155 366, MMV670936 371, MMV897700 418, MMV1576784 515, MMV1579336

In paper but in Fig 7 367, MMV670246

In paper but in Fig 5 525, MMV1579341

Not in paper 380, MMV669848 516, MMV669784

The actual hep numbers need checking for any disagreement between the Master List numbers and the numbers we gotten most recently e.g. in https://github.com/OpenSourceMalaria/Series4/issues/42.

My question is: would the simplest solution here be to add in the compounds to Table 1 along with some hep data? i.e. would that be v annoying? @MedChemProf @cdsouthan It's multiple extra columns: rat and human, CLint and t 1/2 and maybe the "EH" value where we have it. If we're creative with the layout we can probably squeeze it in.

@edwintse did we include hep data for any of these compounds in the bioisostere paper and/or telesubst papers? We'd need to asterisk those numbers with a comment to avoid double-dipping.

The numbers are useful from a compound design perspective and I think we should include at least some, with some summary remarks in the main paper.

While doing this I noticed that OSM-S-366 has, according to the Master List, a potency average of 0.392 uM (from 0.262 and 0.521). In the paper (Table 1) it's listed as 0.92 but in Fig 5 it's listed as 0.79. Anyone have any idea what's happened there?

Hepatocyte Summary June 2022.zip

[cdsouthan]

Hi, adding ~ 10 more structure rows to table 1 with primary activity data should be OK for the illustrious @MedChemProf https://github.com/MedChemProf.

Yours truly can add any that are missing from PubChem if they pass the SID standardizer https://pubchem.ncbi.nlm.nih.gov/standardize/standardize.cgi

However, I suggest adding extra columns where the occupancy is sparse and the units heterogenous will look a bit messy.

Make another small table of just the ADMET type data for these?

Cheers

On Wed, Jun 22, 2022 at 8:17 AM Mat Todd @.***> wrote:

Hi all,

While considering the above question of compound MMV669848 (OSM-S-380) I realised that we have no hepatocyte data in the paper. I looked into this further and according to the Master List we have some such data for 11 compounds. Here is a draft figure that is not complete.

[image: Hepatocyte Summary June 2022] https://user-images.githubusercontent.com/4386101/174967091-4a7127c0-4d67-466b-88d2-41c9b1d4d43d.jpeg

(Chemdraw below if people want to adapt/add).

i.e. the compounds are these:

218, MMV669844 272, MMV639565 353, MMV693155 366, MMV670936 371, MMV897700 418, MMV1576784 515, MMV1579336

In paper but in Fig 7 367, MMV670246

In paper but in Fig 5 525, MMV1579341

Not in paper 380, MMV669848 516, MMV669784

The actual hep numbers need checking for any disagreement between the Master List numbers and the numbers we gotten most recently e.g. in OpenSourceMalaria/Series4#42 https://github.com/OpenSourceMalaria/Series4/issues/42.

My question is: would the simplest solution here be to add in the compounds to Table 1 along with some hep data? i.e. would that be v annoying? @MedChemProf https://github.com/MedChemProf @cdsouthan https://github.com/cdsouthan It's multiple extra columns: rat and human, CLint and t 1/2 and maybe the "EH" value where we have it. If we're creative with the layout we can probably squeeze it in.

@edwintse https://github.com/edwintse did we include hep data for any of these compounds in the bioisostere paper and/or telesubst papers? We'd need to asterisk those numbers with a comment to avoid double-dipping.

The numbers are useful from a compound design perspective and I think we should include at least some, with some summary remarks in the main paper.

While doing this I noticed that OSM-S-366 has, according to the Master List, a potency average of 0.392 uM (from 0.262 and 0.521). In the paper (Table 1) it's listed as 0.92 but in Fig 5 it's listed as 0.79. Anyone have any idea what's happened there?

Hepatocyte Summary June 2022.zip https://github.com/OpenSourceMalaria/OSMSeries4Paper1/files/8955249/Hepatocyte.Summary.June.2022.zip

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[MedChemProf]

@mattodd There is actually a lot to unpack here, but hopefully I will hit all of the points you made.

1) Potency value for OSM-S-366 - I think this was a coincidental mix of a typo in the table (0.92 while changing to two-significant figures from 0.392) and a copy paste error in Figure 5. I will fix both.

2) Adding Hepatocyte data to Table 1 - I agree that things might become too crowded, but I will have a go at modifying the table to incorporate the additional data columns. While attempting this, I may temporarily add duplicate Table 1's to help determine which format might be the best. People can also comment on the comparisons.

3) Compounds with Hepatocyte data that are not currently in Table - I do not think adding some additional compounds to the table would be a problem once the formatting is established. However, I am not sure all of the compounds with hepatocyte data need to be added unless they are necessary for any discussion points in the text. Also to note, the compounds in Table 1 were selected because they contributed to the discussion and also had a mostly complete set of data for the table. I am guessing that many of the newly added compounds will have some gaps for the table.

I will try to stat working on the changes in the near future.

Finally, no problem to continue working on the version on Google Docs, but I thought at one point previously an updated version was being crafted elsewhere for submission to a journal or chemrxiv. Please let me know.

[cdsouthan]

Great, send any new OSM < > SMILES without CID mappings when you can. It takes at least a couple of weeks before new SIDs get fully processed to CIDs

[MedChemProf]

@mattodd I fixed the potency value for OSM-S-368 in Figure 5 and Table 1. Surprisingly Figure 5 had already been corrected at some point earlier and the correct ChemDraw and PNG files were in the GitHub. However, the image did not seem to get pasted into the document.

I am still working on the table, but I am proposing that no new compounds be added. As it stands, if I am able to add additional columns without making it too crowded, two of the nine compounds in the table will have gaps for the hepatocyte and extraction columns (OSM-S-201 ands OSM-S-202). Any additional compounds would then introduce gaps in the HLM, MLM, Solubility or hERG columns.

I am starting to think it might be better to not modify Table 1 and either add a second table that includes the additional metabolic assays to support any new discussion points, or add a table with gaps in the SI.

[MedChemProf]

Please all have a look at the draft Table 1 with added hepatocyte data. Please add any comments, suggestions, etc. as well as any additional compounds that need to be added. Proposed additions to text also being solicited. Thank you. @mattodd @edwintse

[cdsouthan]

Finishing plans? even just > preprint server @mattodd @MedChemProf @edwintse @alintheopen @drc007 AWAK it would be really sad for this to become a dead duck/Labtrove catastrophe/lost data

[cdsouthan]

N.b. this finally came out (took ages....)

https://pubmed.ncbi.nlm.nih.gov/37197802/

Please disseminate. Unfortunately MMV was unaimable to provide the Edinburgh team with funding since last year so we are stuck at 135

• PMID: 37197802
• DOI: 10.1111/bph.16144 https://doi.org/10.1111/bph.16144

Abstract

Antimalarial drug discovery has until recently been driven by high-throughput phenotypic cellular screening, allowing millions of compounds to be assayed and delivering clinical drug candidates. In this review, we will focus on target-based approaches, describing recent advances in our understanding of druggable targets in the malaria parasite. Targeting multiple stages of the Plasmodium lifecycle, rather than just the clinically symptomatic asexual blood stage, has become a requirement for new antimalarial medicines, and we link pharmacological data clearly to the parasite stages to which it applies. Finally, we highlight the IUPHAR/MMV Guide to MALARIA PHARMACOLOGY, a web resource developed for the malaria research community that provides open and optimized access to published data on malaria pharmacology.

Keywords: Plasmodium; bioinformatics; database; drug discovery; malaria; molecular target.

On Wed, Mar 30, 2022 at 6:15 PM Chase Smith @.***> wrote:

All, just as a follow-up, I would be happy to chip-in to try and get over any last hurdles for either the preprint upload or journal submission. Please let me know the status and happy to help. Thanks.

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