Meeting 22 march

[wwjvdsande]

Open Source Mycetoma (MycetOS) Meeting Recurring Meeting Zoom link: https://uni-sydney.zoom.us/j/99281549497

Time: New York 7 AM - UTC 12 noon - London 12 noon - Rotterdam 1 PM - Sydney 11 PM - (2022 schedule discussed below)

Chair: USyd

Minute taker: ErasmusMC

Recording can be found here

Minutes can found below

Link to previous meeting https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/70

Agenda

1. Mechanism of Action of Fenarimols

• [ ] - SSGCID crystal structure
• [x] - @dmitrij176 has finished motif C and D, awaiting on @fantasy121 to complete his and bring it all together into a single overview image. #55
• [x] - @fantasy121 to add all his experimental and characterization data to this document

2. Fenarimol paper writing SI for the next fenarimol paper can be found here (updated by @fantasy121 ) - if you don't have access to this Dropbox file you'll need to ask @wwjvdsande to share it with you. Don't work in the googledox. We will merge both to make it easier.

3. Kinases

   • RIKEN will look in the genome @mattodd and @wwjvdsande (and others) investigate possible funding sources (e.g. GAFFI and DNDi and Eisai ) for kinase chemogenomic set (see https://github.com/OpenSourceMycetoma/What-other-molecules-to-screen/issues/7#issuecomment-1039034999). About £2000-£3000.

4. Other compound series

• Compounds were sent to @MA-Jjingyi and @wwjvdsande by @bebi78,@dmitrij176 and @flavioemery for testing. First results will come in on monday and be presented
• Any other updates (e.g. @AndyBishopSevenoaks)

6. Future Series

@fantasy121 and @kym834 are starting to explore the synthesis of analogues for Series 5 working off the hit compound Fenbendazole/Panacur/MMV003143 Link @kym834 and @fantasy121 is there anything available already? any libraries that we can look into for donations?

[mattodd]

Any chance we can have a rough Agenda, including actions-needing-to-be-chased based on @kym834 's minutes here? People should feel free to highlight anything else of note e.g. recent shipments of new compounds.

[wwjvdsande]

@mattodd @MFernflower agenda is added

[MFernflower]

@wwjvdsande 12 UTC is 8 in new york - is this the correct time?

[wwjvdsande]

@MFernflower in my agenda it states that the meeting starts in an hour from now. I used the link sent by @kym834

[mattodd]

Apologies - I've been called to something else and need to give my apologies for the meeting, but I will catch up with the discussion later on. Hope everyone's well.

[wwjvdsande]

Minutes

Thanks everyone for being there. During this meeting we discussed the following:

1. paper writing: @fantasy121 will update the SAR and move the SAR from the googledocs document to the dropbox document. We will remove the googledocs when the merge has been done to avoid duplications in the future. @Wilson-Lm will double check and update the data from the biological screening

2. Mechanism of Action of the fenarimols

• [ ] SSGCID crystal structure. @wwjvdsande contacted SSGCID and put in a community request for the crystal structure of CYP51 with azoles and fenarimols. The community request was received and sent for approval to NIAID. Will hear on the verdect soon and communicate that to github
• [ ] @dmitrij176 and @fantasy121 finished the SAR and are going to bring it all together into a single overview image. Which will be added to the paper.

3. Kinases

   • [ ] RIKEN will look at the expression of kinases in cultured Madurella mycetomatis and inside the larvae model. @mattodd and @wwjvdsande to approach possible funders (GAFFI and/or DNDi) to purchase the kinase library for screening.

4. New compounds screened

   • [ ] @MA-Jjingyi screened the first compounds and presented the hits during the meeting. The results were obtained from a single experiment and will be repeated to verify. After verification the results will be uploaded in the database
   • [ ] @MA-Jjingyi also noted that for some of the compounds data was missing, which prevented her to screen them. Please double check the data sent with the compounds and add them to the database as well. @dmitrij176 will resend the spreadsheet to @MA-Jjingyi and @wwjvdsande with the data. Suggestion was made to double label tubes (e.g with a sticker and writing directly on the tube)
   • [ ] Does anyone recognize these?
   • [ ] @Kjmondo can you provide the molecular weights of the compounds sent
   • [ ] @AndyBishopSevenoaks any updates?
   • [ ] @fantasy121 and @kym834 are working on series5. @kym834 also looked for available libraries for series5 and will give an update on that.
   • [ ] @dmitrij176 is looking into series6. He is looking to replace some of the rings with azoles. Suggestion was made to see if there are azole libraries with companies (e.g. Johnson & Johnson, MSD or Pfizer) which might already have these kind of molecules and would be able to donate. Azoles are currently in use for many purposes so there should already be plenty of them in literature. Also interesing to see a crystal structure with an active ketoxime in the CYP51 molecule.

5. Perfume compounds @bebi78 to work with two companies - IES-Givaudan (in France) and De Hekserij (A chemical supply house 2 hours away from Erasmus MC). A suggestion was made to ask them to put the compounds MW on the sample tubes to aide screening

[dmitrij176]

Bio assay 2022.docx @MA-Jjingyi @wwjvdsande could you please check the list and let me know which ones you recognise/ have analysed already. If we do it that way it would be easier and faster to identify the missing samples.

[dmitrij176]

For example, there are only 2 entries with a mass of 3 mg: DM40-1 and 44-1.

[MA-Jjingyi]

@dmitrij176 thanks for your help. after checking the compounds we have received, the DM52-1 in your list is different from DM52-2 on the bottle. and the one didn't identify clearly seems like the DM44-1, because the same MW 342.8 and 3mg.

[MFernflower]

@MA-Jjingyi can you upload today's powerpoint?

[bebi78]

@MA-Jjingyi In terms of the natural compounds series, have you identified any inactive compounds? You showed only compounds working at 100 and 25 µM in your presentation and so I wonder which ones are inactive compounds and which ones are just not tested, yet. @MFernflower @mattodd @wwjvdsande Since Ptero-Hepam and the DIM compounds showed activity at 25 µM, is there interest in testing more HDAC inhibitors and/or more DIM-PF derivatives (see also a paper below about antifungal DIMs from 2013)? DIM.antifungal.pdf

[MA-Jjingyi]

Hi,@bebi78 , of course i will update all data about these nature products later. as usual, The MIC test should be repeat 3 times to identify the reality. several MIC tests still need to be done. I will update all data in the GitHub as soon as possible.

[MA-Jjingyi]

Hi,@MFernflower, sorry to reply late. 22032022 MyctOS meeting -MA.pptx these data are just from 1 times test. they need to repeat 3 time as usual. and I will update all data as soon as possible.

[MFernflower]

@bebi78 I think it would be worth waiting for the re-test of DIM before sending more compounds - I do wonder if DIM has a known LD50 in insects considering the eumycetoma animal model is a caterpillar

[MA-Jjingyi]

Hi, @wwjvdsande @bebi78 @MFernflower, the data has already updated in the excel online, including MIC at 100 and 25 uM, MIC and IC50 of MM55 strain. please have a look. The MIC50s will be tested next week. and of course, the left compounds will be tested recently.

[bebi78]

@MFernflower I only found a paper about DIM having estrogenic effects on fish larvae upon chronic exposure.

[MFernflower]

@wwjvdsande @bebi78 Might be worth evaluating DIM in-vivo once larvae season beings