Open Source Mycetoma Meeting 22 Feb 2022

[kym834]

Our next meeting is on Feb 22 and we'll be meeting at

Times: Amsterdam - 10 PM, London - 9 PM, USA (New York) - 4 PM, Sydney - 8 AM (23rd of Feb)

Zoom link: https://uni-sydney.zoom.us/j/99281549497

Chair: UCL

Minute taker: USYD

Recording of this meeting to go [here]

Previous meeting is here (#67)

Agenda

1. Mechanism of Action of Fenarimols

As things stand, there are no crystal structures of madurella proteins and no structures of proteins from other organisms in which are bound fenarimols. Ultimately it would be nice to demonstrate target ID. Question from @mattodd to @wwjvdsande : in theory could you generate a conditional knockdown for Cyp51 and see whether the IC50 for a known active is reduced? This is quite common in malaria.

• [ ] Literature reading needed to see if our SAR agree with exisiting SAR vs same targets in other campaigns. (See Keenan’s SAR papers of fenarimol for Chagas, and other papers). Point of interest for lit reading: Azoles vs fungal cytochrome P450 (CYP51 protein) @dmitrij176 @fantasy121
• [ ] Mechanism of action section of wiki needs updating @dmitrij176 To include potential starting points already mentioned in #67
• [x] @mattodd to update on conversation on crystal structure determination with SSGCID.
• [ ] @wwjvdsande to dig up and share previous computational models created for Cyp51s

2. SAR

Existing analysis in #51

• [ ] @fantasy121 to create a list of targets that arise from this analysis for potential future consideration. e.g. combination of L1 amide linker region with quaternary centre OH.

3. Paper Writing #55

• [ ] Dmitrij and Hung to agree on common grounds for colour-coding visual summaries (threshold or criteria for green/amber/red/black). Keep the visual summary concise and free of clutter such as extended compounds IDs (@mattodd recommends using abbreviated MyOS codes), potency values (use colour coding instead) etc (reserving these for tabulation of data). This conversation should continue at GHI Structural Activity Relationship Analysis of biological evaluation For Fenarimol Analogues/Epichem compounds #51
• [ ] Manuscript needs updates of Chemistry data (Dmitrij ready, Hung to do) @dmitrij176 @fantasy121 #55
• [x] @fantasy121 to forward paper to @alintheopen and Peter Rutledge (can someone please remind us of Peter's Github handle? @pedrochemical!) and ask for edits.

4. Any Further Science Updates from Each Site

• [x] @bebi78 and @flavioemery to update on new shipments to @wwjvdsande #69
• [x] @dmitrij176 to update on shipping of latest compounds. Further discussion of ketoximes (e.g. potency results, E/Z isomerism, mechanism) will take place in a separate repo: https://github.com/OpenSourceMycetoma/Series-1B-Ketoximes)
• [ ] @dmitrij176 to post powerpoint update slides from last meeting in #67.
• [ ] @kym834 mentioned that there was interest at Sydney for high school students to synthesise compounds in the benzimidazole series. @mattodd is also in discussion with @AndyBishopSevenoaks about exactly this and the students are keen to get going.
• [ ] @AndyBishopSevenoaks to advise if he needs any further inputs in advance of lab work starting.

5. Future Series

The importance of combination therapies has been previously mentioned. After fenarimol paper complete we should prioritise new targets as a means to develop molecules that can complement each other. @wwjvdsande mentioned several lines of enquiry that look promising e.g. olorofim (vs DHODH) and the benzimidazoles.

6. Any other business

@OpenSourceMycetoma/corecontrib, please add anything you wish to discuss to the agenda

• [ ] @mattodd to consider how to set up a shared sheet of email addresses for participants and as a means of having people sign up for MycetOS newsletters as we did for OSA.

Next Meeting: March 22nd 2022 - 1 PM EU Remaining Meetings:

4th Tuesday of each month: MAR 22nd 1pm EU APR 26th 10pm EU MAY 1 EU JUNE 10 EU JULY 1 EU AUG 10 EU SEPT 1 EU OCT 10 EU NOV 1 EU DEC 10 EU (but likely no meeting)

Invitations have been sent out. @mattodd asks: can we please finalise the schedule for who does minutes and who hosts each meeting?

7. Action Items for March 2022 Meeting

Action items are those with checkboxes above.

[MFernflower]

Hopefully @bebi78 will be able to attend

[kym834]

Schedule for hosts and minute takes updated for 2022, see #52.

This meeting Host: UCL Minutes: USyd

[flavioemery]

Guys, I couldn't make it today! But I am organizing the compounds data and ask details for shipping soon!

[kym834]

Minutes

Please see above for additional/continuing action items.

1. Mechanism of Action of Fenarimols

• [ ] @mattodd and @wwjvdsande (and others) investigate possible funding sources (e.g. GAFFI and DNDi and Eisai ) for kinase chemogenomic set (see OpenSourceMycetoma/What-other-molecules-to-screen/issues#7). About £2000-£3000.
• [x] @wwjvdsande to explore collaboration with RIKEN to access transcriptomic analysis that might suggest good kinase targets.

SSGCID are open to getting a crystal structure of the protein with small molecule (Itraconazole, Ravuconazole and 2 or 3 fenarimols) bound. Going to ask if they can express the CYP51 protein themselves. Two different proteins but only amino acid different which isn't involved in binding - should we look at both?

• [x] @wwjvdsande to put in request through their website for protein expression

2 & 3. SAR and paper writing

@dmitrij176 has finished motif C and D, awaiting on @fantasy121 to complete his and bring it all together into a single overview image.

• [ ] @fantasy121 to add all his experimental and characterization data to this document

SI for the next fenarimol paper can be found here - if you don't have access to this Dropbox file you'll need to ask @wwjvdsande to share it with you

4. Site updates

@bebi78 sent 51 compounds for testing. These have been received and have been added to the master list. @MA-Jjingyi will test these soon! @dmitrij176 will send a new set of compounds to @wwjvdsande and co. tomorrow #71

• [ ] @MA-Jjingyi to confirm with these have been recieved
• [ ] @flavioemery also has some compounds to contribute. To be shipped and compound data to be posted in issue #69
• [ ] @dmitrij176 add them to the master list when data comes through

We haven't heard from Seven Oaks (@AndyBishopSevenoaks), @mattodd will follow up and see how they are going and if they need any help.

5. Future Series

@fantasy121 and @kym834 are starting to explore the synthesis of analogues for Series 5 working off the hit compound Fenbendazole/Panacur/MMV003143

• [ ] @kym834 and @fantasy121 is there anything available already? any libraries that we can look into for donations?

[MA-Jjingyi]

@dmitrij176 Hi, I just want to check the new mycetoma master list of the new compounds, but I really have no clue to do that. would you like to give me some clue about that. thanks.

[dmitrij176]

@dmitrij176 Hi, I just want to check the new mycetoma master list of the new compounds, but I really have no clue to do that. would you like to give me some clue about that. thanks.

Hi @MA-Jjingyi . Sure. The list attched contains @bebi78 compounds. These are already in the Master List online. Plese bear in mind that several structures in the excel sheet (online) are highlghted in red. I need to change their formulation status to salts and phosphates. Flavios set will be added shortly. I will upload another PDF and let you know in Github. New compounds (MycetOS).pdf .

[dmitrij176]

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

Repository adress

[wwjvdsande]

Good news! Imad Abugessaisa from RIKEN will help us with the transcriptomics.

[MA-Jjingyi]

Hi @dmitrij176 , would you like to add the Molecular Weight of the compounds to the spreedsheet? we need that to dissolve to reach the final concentration. of course, this is the base of our further tests.

[wwjvdsande]

@dmitrij176 the compounds arrived

[dmitrij176]

Hi @dmitrij176 , would you like to add the Molecular Weight of the compounds to the spreedsheet? we need that to dissolve to reach the final concentration. of course, this is the base of our further tests.

Hi @MA-Jjingyi. The MW's were only provided for certain comounds in the original document. I will generate the misssing ones from SMILES and upodate the Master List shortly.

[wwjvdsande]

@mattodd @dmitrij176 @fantasy121 @kym834 @MA-Jjingyi I just put in a request in the SSGCID website for the crystal structure of the CYP51 gene of M. mycetomatis