DNDi Open Synthesis Network

[bendndi]

The first two participating institutions from the DNDi Open Synthesis Network have recieved the preliminary data for the MycetOS project and ahole to initiate work over the Summer:

Illinois Mathematics ans Science Academy (IMSA) https://www.imsa.edu/site_section/discover/ Augusta University https://www.augusta.edu/

Hopefully representatives from both locations will join in on our Github discussions soon!

[Wilson-Lm]

Hey @dmitrij176 , Give me until the end of tomorrow and I will upload the up to date in vitro data for all compounds we tested. I will fill them in the excel sheet we have on github. or do you prefer it if I email you an excel sheet? The in vivo data will have to wait a little bit longer as we're still currently running the experiments.

[dmitrij176]

Hi again @Wilson-Lm . Ok, thanks a lot. Upload whichever way you prefer, all options are suitable.

[dmitrij176]

Hi @Wilson-Lm. Any news on the in vitro and in vivo data?

[Wilson-Lm]

Hi @dmitrij176, I have updated the in vitro data in the main file on github (my apologies for forgetting to tell you). The data is up to date. In vivo data however is still not ready. I am running the last larvae experiment to re-confirm the hits we have found. I will be able to give an update on that in the next meeting. The weather has been quite forgiving lately and thus we are able to stretch out the larvae experiment this year. From experience in the past few years, normally we wont be able to do that in November. Fingers cross we'll get a clearer view on how the compounds fair in this last larvae run!

[dmitrij176]

Hi @dmitrij176, I have updated the in vitro data in the main file on github (my apologies for forgetting to tell you). The data is up to date. In vivo data however is still not ready. I am running the last larvae experiment to re-confirm the hits we have found. I will be able to give an update on that in the next meeting. The weather has been quite forgiving lately and thus we are able to stretch out the larvae experiment this year. From experience in the past few years, normally we wont be able to do that in November. Fingers cross we'll get a clearer view on how the compounds fair in this last larvae run!

Thanks a lot. Do you think that youll be able to get all the in vivo data by next meeting (scheduled on Nov 24th)? I just need to understand how to finish my conclusions in the upcoming upgrade report i.e with just in vitro or together with larval assays.

[Wilson-Lm]

I

Hi @dmitrij176, I have updated the in vitro data in the main file on github (my apologies for forgetting to tell you). The data is up to date. In vivo data however is still not ready. I am running the last larvae experiment to re-confirm the hits we have found. I will be able to give an update on that in the next meeting. The weather has been quite forgiving lately and thus we are able to stretch out the larvae experiment this year. From experience in the past few years, normally we wont be able to do that in November. Fingers cross we'll get a clearer view on how the compounds fair in this last larvae run!

Thanks a lot. Do you think that youll be able to get all the in vivo data by next meeting (scheduled on Nov 24th)? I just need to understand how to finish my conclusions in the upcoming upgrade report i.e with just in vitro or together with larval assays.

I wont be able to give the full data as this last larvae experiment will run till 27th of November. However, I reckon the data that I will show will most likely represent how the end results look like. I am hoping that this last run wont give us a completely different data pattern.

[dmitrij176]

Hi @Wilson-Lm. Hope you had a good Christmas break. Just wanted to check with you if there are any news regarding in vivo data from the latest assays? Will there be updates on the Master List?

[Wilson-Lm]

Hi @Wilson-Lm. Hope you had a good Christmas break. Just wanted to check with you if there are any news regarding in vivo data from the latest assays? Will there be updates on the Master List?

Hi Dimitrij, Happy New Year! The newest data can be found in the spread sheet, in the MyOS compounds and Pandemic Box sheet. Log-Rank and % survival data was updated. For the MyOS compounds, 1 compound - DM7-1 significantly increased survival, and in the Pandemic Box, we found 4 that increased survival - Olorofim, Fenbendazole, MMV1782387, Ravunonazole. I have the LogD data for pandemic box compounds but not for the fenarimol analogues.

[dmitrij176]

Hi Hung (@fantasy121 ). Hope all is going well in Sydney. I have assigned MYOS codes to novel Fenarimols in the Master List (https://docs.google.com/spreadsheets/d/1YhK-3i2KwuVabo1GbZSgVjAUbavEICCMKi5v-EhNq80/edit#gid=954203120) and need to reconfirm some details with you. I came across some molecules of yours which either did not have SMILES or there was an uncertainty regarding the batch number (due to your internal coding). To simplify things, I want to provide you with specific details which would help to navigate you. All unresolved Fenarimols are highlighted in red. Summary: Row 5: EPL-BS0495. I've put it as a second batch (last two digits in the MYOS code) but wasnt sure, since the same molecule appeared in row 3 (assigned as first batch). Rows 16, 33, 34: Batch issue. Rows 134-138: SMILES missing, so could not reconfirm the structure. Ive put them as free bases. Just check please.

If you have any questions, let me know. Thanks

[fantasy121]

@dmitrij176, all of my alcohol fenarimol analogues should appear as protonated alcohols (OH) and not free bases (O-). I think the missing H is an artefact of the digital text-to-structure rendering of SMILES strings. As my work up is water, all O- should be protonated.

The F or P notations following my internal codes refer to the fractions that the desired compounds were eluted from the column. F notation was used for all compounds in 2017 (HPD01-X to HPD30-X) and P notation was used for all current molecules (HPD031-X onwards). For my current notations, I have also added an extra zero in the hundred position to accomodate for future compounds (HPD30-X old system vs HPD031-X new system).

As you have come across HPD28-1 (4-fold racemate) where the structure is as follows: I resolved the two pairs of isomers: F2 is RR and SS isomer pair(themselves are still 2-fold racemic) F3 is the RS and SR isomer pair (themselves are still 2-fold racemic)

HPD28-1F2 and HPD28-1F3 are distinct isolated novel products and must not be merged. I think their isomer identity got left behind when they were appropriated into the spreadsheet. I will go ahead and add that info back. I also updated new SMILES strings to accurately reflect the isomers

This is why I now include fractions as a suffix (F or P) for my codes, for absolute clarity, and to avoid confusion when I happen to get out multiple desired products in one reaction. Please keep the F/P suffix so we can refer to my work in LabArchives and thesis if necessary.

Confirm Row 3 is synthesised by me because that is how I label my resynthesis compound in the ID column where I put my internal code first (HPD14-1), then the compound I'm trying to resynthesise (EPL-BS0495).

Row 5 is most likely acquired from the Epichem library (you can see in the "by whom" column my name is not there). @wwjvdsande @Wilson-Lm @mattodd can you double check this?

I think the original purpose of row 3 vs row 5 is to see whether I could replicate the efficacy of the Epichem compound.

Yes to row 16 HPD17-2F3. Keep as is, product is from eluted fraction 3 of the repeated reaction HPD17-2.

I have put the SMILES strings in for Row 134 to 138. NB: Row 134 is not EPL-BS0495, not sure why it says so (as clarified above, EPL-BS0495 corresponds to HPD14-1 on rows 3 and 5. HPD14-1 is my attempt at resynthesising EPL-BS0495). Row 134 (HPD033-2P4) is a novel compound. I have removed this inaccurate piece of information from row 134.

For future references, if you need a quick double check of data for my compounds, or if you're in a rush and need to access a snapshot of everything I did the the lab (and where I'm not there to answer right away) you can consult this page which should have most of the relevant things pertaining to the molecules I'm making including structures, names, my codes and SMLES. Hope this helps. https://au-mynotebook.labarchives.com/share/Hung%2520Duong%2520-%2520PhD/Mi42fDY4MTUwLzIvVHJlZU5vZGUvNDczMzQ5ODkyfDYuNg==

Hope this helps

[dmitrij176]

@dmitrij176, all of my alcohol fenarimol analogues should appear as protonated alcohols (OH) and not free bases (O-). I think the missing H is an artefact of the digital text-to-structure rendering of SMILES strings. As my work up is water, all O- should be protonated.

The F or P notations following my internal codes refer to the fractions that the desired compounds were eluted from the column. F notation was used for all compounds in 2017 (HPD01-X to HPD30-X) and P notation was used for all current molecules (HPD031-X onwards). For my current notations, I have also added an extra zero in the hundred position to accomodate for future compounds (HPD30-X old system vs HPD031-X new system).

As you have come across HPD28-1 (4-fold racemate) where the structure is as follows: I resolved the two pairs of isomers: F2 is RR and SS isomer pair(themselves are still 2-fold racemic) F3 is the RS and SR isomer pair (themselves are still 2-fold racemic)

HPD28-1F2 and HPD28-1F3 are distinct isolated novel products and must not be merged. I think their isomer identity got left behind when they were appropriated into the spreadsheet. I will go ahead and add that info back. I also updated new SMILES strings to accurately reflect the isomers

This is why I now include fractions as a suffix (F or P) for my codes, for absolute clarity, and to avoid confusion when I happen to get out multiple desired products in one reaction. Please keep the F/P suffix so we can refer to my work in LabArchives and thesis if necessary.

Confirm Row 3 is synthesised by me because that is how I label my resynthesis compound in the ID column where I put my internal code first (HPD14-1), then the compound I'm trying to resynthesise (EPL-BS0495).

Row 5 is most likely acquired from the Epichem library (you can see in the "by whom" column my name is not there). @wwjvdsande @Wilson-Lm @mattodd can you double check this?

I think the original purpose of row 3 vs row 5 is to see whether I could replicate the efficacy of the Epichem compound.

Yes to row 16 HPD17-2F3. Keep as is, product is from eluted fraction 3 of the repeated reaction HPD17-2.

I have put the SMILES strings in for Row 134 to 138. NB: Row 134 is not EPL-BS0495, not sure why it says so (as clarified above, EPL-BS0495 corresponds to HPD14-1 on rows 3 and 5. HPD14-1 is my attempt at resynthesising EPL-BS0495). Row 134 (HPD033-2P4) is a novel compound. I have removed this inaccurate piece of information from row 134.

For future references, if you need a quick double check of data for my compounds, or if you're in a rush and need to access a snapshot of everything I did the the lab (and where I'm not there to answer right away) you can consult this page which should have most of the relevant things pertaining to the molecules I'm making including structures, names, my codes and SMLES. Hope this helps. https://au-mynotebook.labarchives.com/share/Hung%2520Duong%2520-%2520PhD/Mi42fDY4MTUwLzIvVHJlZU5vZGUvNDczMzQ5ODkyfDYuNg==

Hope this helps

Yes, thanks Hung (@fantasy121). To be fair, I actually visited your Labarchive, but the Honours version as some of the mentioned analogs refer to legacy database. Anyway, all is sorted now, so no problems. Indeed, stereochemistry needs to be taken into account. Same refers to formulations (bases, salts, alcohols etc.). I will update everything accordingly.