Open Source Mycetoma (MycetOS) Meeting Jan 26/27 2021

[mattodd]

Further to confirmation of meeting times (here) and previous meetings (#28) and previous meeting (#39) recording?, we're all meeting up Jan 26/27 at Zoom ID: 992-8154-9497 https://uni-sydney.zoom.us/j/99281549497.

Agenda Items:

Science updates from different sites. Current needs Potential applications for research funds. Newsletter and World NTD day

Anything else? @OpenSourceMycetoma/CoreContrib

**Meeting was held. Recording is here

Key take homes (please comment/add if anything omitted):

Wilson presented data on in vivo evaluation of in vitro actives from Pathogen Box. Four compounds looking good: olorofim (DHODH inhibitor), MMV1782387, X and Y <-- which are these? Also presented data on recent MycetOS submitted compounds. No breakthrough potencies observed, though it should be noted that compound is given only for the first 3 days.

Tafenoquine is interesting since it inhibits other mycetoma causative agents. Including species of Medicopsis and Falciformispora that are resistant to other drugs. That is fascinating.

Combinations of molecules could be considered for investigation, though in vitro when this has been tried there has been no obvious synergy. @MFernflower suggested daraprim - has it been investigated? Olorofim hits pyrimidine nucleobase synthesis and daraprim hits purine nucleobase synthesis.

It is essential that we compare three values: in vitro potency (which includes penetration of fungal cell, and for which we now have 150 values!), in vivo AUC (which includes penetration of grain) and a physicochemical property such as logD. Such comparisons likely to be most productive for compounds sharing structural class and/or mechanism of action. A comparison of the structures of the in vivo actives may reveal structural features that are shared by actives. If there is a trend observed, we can always go back to the Epichem library and source more compounds.

Note current logD values incomplete and some have been calculated with different software, e.g. from COADD website. We need consistency in the values, and will ask @bendndi to help with these calculations.

Kimberly's been doing synthesis on Series 2 (OpenSourceMycetoma/Series-2-Aminothiazoles#4). Keeping an eye on other/commercial availability (OpenSourceMycetoma/Series-2-Aminothiazoles#2).

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) Newsletter #43 needs people to add/edit, and we need a sign-up list #42. @fantasy121 has the Gmail sign-in details, and Dana can help if it's hard. @kym834 agreed to take care of this in advance of World NTD day (this coming Saturday). We could use everyone's help in promoting MycetOS on Saturday.

4) Question for @wwjvdsande and @Wilson-Lm do we have potency data for the compounds that were sent in from the University of Ghana?

• [x] ACTION ITEM: Wilson to post meeting slides and ensure in vivo data in the Master List.
• [ ] ACTION ITEM: Hung 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: Ben Perry: once Master List is up to date, ensure logD values calculated for all compounds Wendy and Mat keep an eye on funding sources, e.g. HFSP, EU.
• [x] ACTION ITEM: Kymberley to update series 2 repository.
• [ ] ACTION ITEM: All: use MycetOS molecule numbering system, #44.
• [x] ACTION ITEM: All to contribute comments to the newsletter that is going out on Saturday, #43.
• [x] ACTION ITEM: Kymberley to set up email newsletter sign up page, #42.
• [x] ACTION ITEM: Hung to post this meeting to YouTube and insert link above.

Next meeting: February 23rd 2021 - calendar files are here.

[Wilson-Lm]

As promised, the latest in vivo figures for both fenarimol analogues and pandemic box. Data can be found in our main excel sheet in GitHub. fenarimol 2021 meeting 1.pptx

[MFernflower]

@Wilson-Lm @wwjvdsande Just wanted to confirm the name of the drug resistant fungus that you found tafenoquine was able to kill

It was the genus Medicopsis in the order Pleosporales correct?

[Wilson-Lm]

@Wilson-Lm @wwjvdsande Just wanted to confirm the name of the drug resistant fungus that you found tafenoquine was able to kill

It was the genus Medicopsis in the order Pleosporales correct?

@MFernflower That is correct. Medicopsis romeroi of the Pleosporales! and also Falciformispora senegalensis of the same order.

[Wilson-Lm]

in vitro and in vivo potency results + misc information have been included and updated in the main excel file, sheet In vitro & vivo potency & LogD values That includes compounds that are active in vitro and also compounds that underwent in vivo screening.

[MA-Jjingyi]

Hi,Wlison. good morning. it's my main topic of my next research, right? oh ,my goodness. I must learn more technics about them in the near future, i think! thanks again.

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From: Wilson notifications@github.com Sent: Thursday, January 28, 2021 7:10 PM To: OpenSourceMycetoma/Series-1-Fenarimols Series-1-Fenarimols@noreply.github.com Cc: M. Jingyi m.jingyi@erasmusmc.nl; Manual manual@noreply.github.com Subject: Re: [OpenSourceMycetoma/Series-1-Fenarimols] Open Source Mycetoma (MycetOS) Meeting Jan 26/27 2021 (#45)

in vitro and in vivo potency results + misc information have been included and updated in the main excel file, sheet In vitro & vivo potency & LogD values That includes compounds that are active in vitro and also compounds that underwent in vivo screening.

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