Open Source Mycetoma (MycetOS) Meeting Feb 23 2021

[mattodd]

Further to confirmation of meeting times (here) and previous meetings (#28) and previous meeting (#45) recording?, we're all meeting up Feb 23 at Zoom ID: 992-8154-9497 https://uni-sydney.zoom.us/j/99281549497.

Meeting recording Link to go here:

Agenda

1) Outstanding action items from #45:

• [x] ACTION ITEM: @fantasy121 to assemble Chemdraw of all structures evaluated in vivo along with the in vivo AUC values to see if patterns can be seen.
• [ ] ACTION ITEM: @bendndi: once Master List is up to date, ensure logD values calculated for all compounds (someone needs to ask Ben very nicely for this)
• [x] ACTION ITEM: @kym834 to update series 2 repository.
• [ ] ACTION ITEM: All: use MycetOS molecule numbering system, #44. <--volunteer to ensure this is installed somewhere central, e.g. in Techops repo.
• [x] ACTION ITEM: @fantasy121 to post this meeting to YouTube and insert link in #45.

Newsletter was created and sent out #43. Everyone should keep in mind items for the next one, which we should send out in March or April.

2) Science updates from different sites.

• Any updates to Wilson Lim's previous dataset?
• Do we have potencies for the Ghana compounds?
• Any action needed on daraprim, Tafenoquine or DHODH inhibitors?
• Any need to go back to Epichem to source remaining fenarimols for the paper?
• Kymberly series 2.

3) Current general project needs

• schedules for biological testing

4) Anything else to discuss? @OpenSourceMycetoma/CoreContrib

AOB

1) @wwjvdsande and @mattodd continue to seek project funding, but are interested in any potential sources. It is essential we generate resources to keep the science moving.

2) We have adopted the new molecule numbering system (#44), and we should now be using this. As discussed, we can use simple codes for structures, but the full codes include batch and salt. Compounds can be added when in the planning stages, but then a new column will be needed in the Master List to indicate (with a "0") that it is not yet made (when it receives a "1" in that column).

3) Need a volunteer to assemble this agend for the next meeting:

Next meeting: March 22nd or 23rd (??) 2021 - calendar files are here. As per image below, I've two slots come up.

[kym834]

I've updated the series 2 repo - will discuss in meeting. I have meeting for Tuesday 23rd

[kym834]

Meeting Minutes Recording is here

Please add or edit anything omitted

1) @kym834 gave update on series 2 proposed synthesis route (see https://github.com/OpenSourceMycetoma/Series-2-Aminothiazoles/issues/4 for details). If synthesis goes as planned, it will be run with SSP students at the University of Sydney in April-May 2021.

2) Outstanding from last time - evaluated in vivo along with the in vivo AUC values to see if patterns can be seen. @fantasy121 and @dmitrij176 have both looked at their own compounds but still missing some data. @wwjvdsande and co. are going to explore AUC at different times and chose the best of the following options day 3 - last day of treatment, day 4 - first day after treatment and day 10 - final day of study.

3) Related to 3 - for logD values @bendndi can calculated them very quickly but only if the compound SMILES ARE SENT IN A TABLE. Master list needs to be check to insure it is up to date and the link sent to @bendndi who will kindly populate the logD values.

@bendndi it sounded like it was quite simple to do this if you have the smiles. Our priority is to get the logD for fenarimols compounds. But if its easy and quick enough would you be able to do this for all of the compounds we have so far including the pandemic box etc?

4) Any action needed on daraprim, Tafenoquine or DHODH inhibitors? - Tafenoquine good activity primaquine not so good why? need to look into SAR and property relations. Possible project for collabs (see AOB). Olorofin (DHODH inhibitor) might be worth looking into in vivo activity at other concentrations then we have tested or as a combination therapy.

5) Ghana compounds - none that exhibited high levels of potency (@Wilson-Lm can you share the data below?)

6) Schedule for biological testing in 2021 - in vitro can be done year round. If you would like your compounds tested in vitro and in vivo in 2021 they must be shipped to @wwjvdsande and co. before the 1st of July.

7) Any need to go back to Epichem to source remaining fenarimols for the paper? - will address these next meeting once we analysis of the final data (still to be updated in master list) has been completed

AOB

• Collaboration on the horizon with Dr Kaitlin Beare who is at The University of Auckland to do some data analysis of the compounds we have tested in vitro and in vivo. Won't be until later this year. USyd to keep team updated. @wwjvdsande also has a chat planned with another possible collaborator to also work on some data analysis. If anyone has any specific questions or trends they would like to be looked at post below so we can start creating a list of possibilities. Note that as a teaching activity could open up new funding opportunities.
• Novel MOAs - Potential of a new mode of action for us to discover from the novel compounds we have synthesised and tested. Want to try and fill in any blanks we have for those compounds with high potency in vivo. If you find anything please comment below as it can be added into the table @Wilson-Lm has for these compounds. Transcriptics might help us to identify possible MOA for compounds we think might have a novel MOA. Common knockout methods are not so useful for fungal diseases.

Next meeting Time slot B (New York 3 pm Tuesday March 23rd – Amsterdam 9 pm Tuesday March 23rd – Sydney 7 am/8 am Wednesday March 24rd – London 8 pm Tuesday March 23rd).

Action items:

• [ ] @fantasy121 and @dmitrij176 to collate a table of their compounds with the columns personal code, MYOS code, smile string and logD and send to @Wilson-Lm and co. to get data on AUC values. If you don't have the logD leave blank until we get the values from @bendndi.
• [ ] @wwjvdsande, @Wilson-Lm to update AUC values in master list based on their decision for best day to calculate them at.
• [ ] @Wilson-Lm to double check master list and send to @bendndi to populate with logD values.
• [ ] Volunteer to combine all sheets in the master worksheet into a single living master sheet noting the box or who synthesised the compound in the by whom column.
• [x] @wwjvdsande to contact MMV to see if they have any literature on the MOA of any of the MMV compounds we have got as hits. (Wendy has already contacted them (see bottom of #28)
• [ ] Any volunteer to post agendas before meetings?
• [ ] All: use MycetOS molecule numbering system, #44. <--volunteer to ensure this is installed somewhere central, e.g. in Techops repo.

[dmitrij176]

@bendndi further to our meeting discussion, could you please do the logD calculations for MYOS compounds (Fenarimols). Here is the link to the Master List:

https://docs.google.com/spreadsheets/d/1YhK-3i2KwuVabo1GbZSgVjAUbavEICCMKi5v-EhNq80/edit#gid=954203120

All the information (including SMILES) is up to date and the excel file is downloadable.

[mattodd]

@kym834 great minutes and actions - thank you for assembling, really helpful and important to do.

[bendndi]

@dmitrij176 Done, also added in logP, rotatable bonds and flexibility value. Note however that there are two compounds with the same mycetos ID and this needs to be resolved asap (MYOS_00018_00_01)

Once you have this resolved I'll calculate the logD etc for the one of these two compounds for which it is missing.

[dmitrij176]

@bendndi the duplicate issue has been resolved, thank you for spotting that. These compounds are two separate entries now, so only MYOS_00019_00_01 needs physiochemical calculations.

While going through the list yesterday, I have identified another mismatch in several entries:

The SMILES generated different structures in Chemdraw, so there are 2 problems arising from that: 1. MYOS are no longer valid because MYOS_00001_00_01 refers only to HPD14-1 (rows 3 and 5) 2 HPD033-2P4 and HPD033-3P3 apparently are different molecules unless there is a mistake. @fantasy121 can you have a look and let me know.

Rows 3-133 are up to date now and the rest will be adjusted after we resolve remaining mistakes in the list

[Wilson-Lm]

Hi @bendndi, Thank you for calculating the LogD and P values for the fenarimol analogues, Could you also do the logD calculations for compounds in the pandemic response box? they are here: https://docs.google.com/spreadsheets/d/1YhK-3i2KwuVabo1GbZSgVjAUbavEICCMKi5v-EhNq80/edit#gid=208916183 Thank you!

[dmitrij176]

@bendndi the duplicate issue has been resolved, thank you for spotting that. These compounds are two separate entries now, so only MYOS_00019_00_01 needs physiochemical calculations.

While going through the list yesterday, I have identified another mismatch in several entries:

The SMILES generated different structures in Chemdraw, so there are 2 problems arising from that: 1. MYOS are no longer valid because MYOS_00001_00_01 refers only to HPD14-1 (rows 3 and 5) 2 HPD033-2P4 and HPD033-3P3 apparently are different molecules unless there is a mistake. @fantasy121 can you have a look and let me know.

Rows 3-133 are up to date now and the rest will be adjusted after we resolve remaining mistakes in the list

@fantasy121, I have only managed to find HPD033-1 in your ELN which is the same as the cyclohexane product. But again, is it 2P4 or 3P3? And what about the middle one? Definitely its a different structure. Can you check please

[mattodd]

Hi all (@OpenSourceMycetoma/corecontrib) in advance of the next meeting (Tue evening this week UK time), could people please browse the above minutes and action items and try to address things that are still needed? Also, are there any volunteers to create a new Issue containing the outstanding action items, using the above as a template? @fantasy121 @kym834 @dmitrij176 @Wilson-Lm ? I would do it myself, but I feel as though I would like to share the joy.

[MFernflower]

@mattodd I don't seem to have a time for Tuesday's (In the US and UK) meeting

[kym834]

Hi @MFernflower,

Times for our next meeting are: Time slot B (New York 3 pm Tuesday March 23rd – Amsterdam 9 pm Tuesday March 23rd – Sydney 7 am/8 am Wednesday March 24rd – London 8 pm Tuesday March 23rd). Also written above in the minutes :)