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OpenSourceMycetoma / Monthly-zoom-meetings

Since MycetOS is diversifying we decided as from 2023 to place the monthly meetings no longer under a compound series but separately in this repository.
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Monthly Mycetoma Meeting 28th November 2023 (NO MEETINGS UNTILL 2024) #14

Open mattodd opened 11 months ago

mattodd commented 11 months ago

Time: Nov 28th, 12 noon UK, 1pm EU, 11pm Aus, 7am EDT (Timezones)

The Outlook invite can be found here

Location: https://uni-sydney.zoom.us/j/99281549497. In case of failure, use https://ucl.zoom.us/j/99789829423 and in case of double failure use MycetOS meeting teams link Chair: USyd Minute taker: UCL Previous meeting #13 Recording: Present: Apologies:

AGENDA

**In vitro screening**

Series 1 - Fenarimols

SCYX0001335912 EPL-BS0197 Shipped to TCG for DNDi SCYX0001574838 EPL-BS0792 Shipped to TCG for DNDi SCYX0001338488 EPL-BS0216 Shipped to TCG for DNDi SCYX0001336037 EPL-BS0213 Shipped to TCG for DNDi SCYX0001388141 EPL-BS0241 Shipped to TCG for DNDi

Of the remainder, two are not available:

SCYX0001322027 EPL-BS0158 Vial not found likely in other boxes requiring further investigation SCYX0001268121 EPL-BS0093 Sample consumed No stock remaining

Four were possibly available, but James has now confirmed that

SCYX0001294212 EPL-BS0121 Sample available at Epichem and TCG SCYX0001278548 EPL-BS0105 Not available either at Epichem or TCG SCYX0001315839 EPL-BS0143 Not available at Epichem, might be available at TCG SCYX0001255546 EPL-BS0039 Not available either at Epichem or TCG

@wwjvdsande has reported data for the first five compounds:

SCYX0001335912 EPL-BS0197 not inhibited at 100 uM SCYX0001574838 EPL-BS0792 not inhibited at 100 uM SCYX0001338488 EPL-BS0216 inhibited at 100 and 25 uM SCYX0001336037 EPL-BS0213 inhibited at 100 and 25 uM SCYX0001388141 EPL-BS0241 inhibited at 100 and 25 uM

Fenarimol Paper

most recent file version on Dropbox: Fenarimol Paper October 3rd V2.2, 25th Nov

Highlighting recent hits in this series: from @MA-Jjingyi latest data, it would be helpful to have a diagram with structures. MYOS00510 and MYOS00518 were hits? Do recently-tested compounds need to be incorporated in the fenarimol manuscript? New SAR diagrams ideally need to be added to the wiki with codes, or we risk missing key insights from the new data.

Examples: Data from Sept 21

[ ] Modelling: @meh-cyprian to proceed to try to model fenarimol compounds in potential protein target (described here or to clarify what more data are needed. Aim is to better understand the SAR via docking vs homology model of protein. @mattodd reached out to @gemmaturon and @miquelduranfrigola who may present the work that was done with @meh-cyprian

Siderophores:

Fluoroscent siderophore was tested in the larvae in the last weeks of the season.

Series 2 - Aminothiazoles

Molecules made by UCL MSc cohort (23 entries) were shipped to Erasmus MC for testing. Also Whitgift compound (MYOS_0590_00_01).

@KlementineJBS wrote a guide on the Wiki on how to share compounds in a way that will hopefully prevent duplication of both compounds themselves and MYOS codes. Also posted some compounds to be made next here.

Series 5 - Benzimidazoles Good potencies were observed for recent compound batches of benzoxazoles (e.g. here). These resemble the benzimidazoles which have shown potent in vivo efficacy.

Testing is ongoing. So far MYOS00527 was the only hit.

Some oxazoles will be tested against Falciformispora senegalensis too (by whom?). This series will be evaluated in vivo in the new larval season - is this still to be done?

More benzoxazoles: @AndreaOtago says that the CHEM 305 students will be making more benzoxazoles in April 2024 as part of their lab project. @dosreic suggested doing some PK 'SAR' follow up analogues so this could inform both DNDi's project and this project. @dosreic to follow up the DMPK results.

Series 6: ketoximes

Latest compound shipment https://github.com/OpenSourceMycetoma/Series-6-Ketoximes/issues/5, to be tested by @MA-Jjingyi.

@bebi78 had suggested evaluating different salts of the ketoximes, still of value for future. Perhaps this can go on the wiki under future plans?

Series 3: Tricyclics/Phenothiazines

**Global Health Priority Box***

This has been tested and reported by @MA-Jjingyi here. Three compounds were taken on to in vivo testing. Outcome is some promise for compound MMV1804559.

Kinase inhibitor library.

The KCGS library was screened. Additional drugs of similar classes were sent by @bebi78 and screened by @marijschippers. In total 6 drugs from the KCGS appeared to be hits along with one from the package sent by @bebi78.

Bioinformatics

Plant Extracts from Nigeria

Further to the conversation here we need to establish

Misc updates:

Next Meetings

To be discussed for 2024. Timings raised here

Looks like there is preference for: Even months: New York 8:00, London 12:00, Europe 13:00, Sydney 23:00 (european wintertime) and New York 7:00, London 12:00, Europe 13:00, Sydney 21:00 (european summertime) Odd months: Option D: New York 16:30, London 20:30, Europe 21:30, Sydney 07:30 (european wintertime) and New York 15:30, London 20:30, Europe 21:30, Sydney 5:30 (european summertime).

We need a volunteer to:

MFernflower commented 11 months ago

@lferrins did you find that single lost entry when I moved all the data over? I only had 14 entries in final file

On Mon, Nov 27, 2023, 2:48 PM Mat Todd @.***> wrote:

Compiling agenda ready for meeting... This post is draft until this text is removed

Time: Nov 28th, 12 noon UK, 1pm EU, 11pm Aus, 7am EDT (Timezones https://www.timeanddate.com/worldclock/meetingdetails.html?year=2023&month=11&day=28&hour=12&min=0&sec=0&p1=233&p2=136&p3=37&p4=771&p5=235&p6=152&p7=770&p8=250&p9=196&p10=240 )

The Outlook invite can be found here https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/files/9674081/Monthly.MycetOS.meeting00.zip

Location: https://uni-sydney.zoom.us/j/99281549497. In case of failure, use https://ucl.zoom.us/j/99789829423 and in case of double failure use MycetOS meeting teams link https://teams.microsoft.com/l/meetup-join/19%3ameeting_M2I2MDcxZTgtYjZjOS00YTdmLTgwZTMtNWQ3OTc4NDY0MDNj%40thread.v2/0?context=%7b%22Tid%22%3a%22526638ba-6af3-4b0f-a532-a1a511f4ac80%22%2c%22Oid%22%3a%22a5ed84b8-5af1-42c6-9f8d-240f23a5d997%22%7d Chair: USyd Minute taker: UCL Previous meeting #13 https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/13 Recording: Present: Apologies:

AGENDA

In vitro screening

Series 1 - Fenarimols

SCYX0001335912 EPL-BS0197 Shipped to TCG for DNDi SCYX0001574838 EPL-BS0792 Shipped to TCG for DNDi SCYX0001338488 EPL-BS0216 Shipped to TCG for DNDi SCYX0001336037 EPL-BS0213 Shipped to TCG for DNDi SCYX0001388141 EPL-BS0241 Shipped to TCG for DNDi

Of the remainder, two are not available:

SCYX0001322027 EPL-BS0158 Vial not found likely in other boxes requiring further investigation SCYX0001268121 EPL-BS0093 Sample consumed No stock remaining

Four were possibly available, but James has now confirmed that

SCYX0001294212 EPL-BS0121 Sample available at Epichem and TCG SCYX0001278548 EPL-BS0105 Not available either at Epichem or TCG SCYX0001315839 EPL-BS0143 Not available at Epichem, might be available at TCG SCYX0001255546 EPL-BS0039 Not available either at Epichem or TCG

  • @dosreic https://github.com/dosreic to investigate whether it is possible to have SCYX0001294212 EPL-BS0121 and SCYX0001315839 EPL-BS0143 shipped from TCG to Wendy.

@wwjvdsande https://github.com/wwjvdsande has reported data https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/12#issuecomment-1828164980 for the first five compounds:

SCYX0001335912 EPL-BS0197 not inhibited at 100 uM SCYX0001574838 EPL-BS0792 not inhibited at 100 uM SCYX0001338488 EPL-BS0216 inhibited at 100 and 25 uM SCYX0001336037 EPL-BS0213 inhibited at 100 and 25 uM SCYX0001388141 EPL-BS0241 inhibited at 100 and 25 uM

-

@fantasy121 https://github.com/fantasy121 to add these compounds to the Master List and generate MyOS codes and send to @MA-Jjingyi https://github.com/MA-Jjingyi

@MA-Jjingyi https://github.com/MA-Jjingyi to advise whether more data coming on these compounds

From the synthesized compounds (which?) several have been screened. MYOS00510 and MYOS00518 were hits. [ ] @meh-cyprian https://github.com/meh-cyprian to proceed to try to model fenarimol compounds in potential protein target OpenSourceMycetoma/Series-1-Fenarimols#68 (comment) https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/68#issuecomment-1546869698, or to clarify what more data are needed. Aim is to better understand the SAR via docking vs homology model of protein. --> no news yet. We need to contact them one more time. @mattodd https://github.com/mattodd will do.

Paper: is the paper ready for everyone to read it one more time and then submit? --> version 3 oct was the latest version in dropbox. Hung updated the writing. What is still needed are the concluding remarks. So what is known on CYP51. Do our results link to data what is known on Cyp51? May be look at the azoles. So do @dmitrij176 https://github.com/dmitrij176 or @fantasy121 https://github.com/fantasy121 already have this in the discussion of their thesis. If so can this be added to the paper. Also the coding of the compounds needs addressing. We were using MYOS codes as numbering. This is also useful for those who want to look them up in the MycetOS spreadsheet. However the intermediate ones are currently numbered as Int#. Conclusion lets use Int for the intermediate ones.

Siderophores: Fluoroscent siderophore was tested in the larvae in the last weeks of the season.

  • The results need to be processed. --> need to correct for autofluorescence

Series 2 - Aminothiazoles @KlementineJBS https://github.com/KlementineJBS is the corresponding researcher for this project at USyd. @KlementineJBS https://github.com/KlementineJBS has updated the Wiki https://github.com/OpenSourceMycetoma/Series-2-Aminothiazoles/wiki/All-Compounds-Made-To-Date with the compounds successfully synthesised by USyd in June.

Molecules made by UCL MSc cohort (23 entries) have been shipped to Erasmus MC for testing. Same applies for selected Whitgift compound (MYOS_0590_00_01). The compounds were diluted and a first screening was performed. The results will be uploaded this week on the spreadsheet.

MYOS-codes. The team at ErasmusMC lost a lot of time figuring out which compounds where which due to the renumbering of compounds and the duplication of numbers. Please, before shipping any compounds make sure that the MYOS codes are already in the spreadsheet and correct. Problem now was that compounds were sent before they were entered in the spreadsheet and therefore the same codes where used by others too. This is confusing and prone to mistakes! The numbering convention is at https://github.com/OpenSourceMycetoma/MycetOS-Tech-Ops/wiki/The-Molecule-Numbering-Convention --> the renumbering was also done on the vial itself to avoid problems in the future when compounds need to be rescreened. For numbering. On ( https://github.com/OpenSourceMycetoma/Series-2-Aminothiazoles/wiki) it is explained on how to do this.

Series 5 - Benzimidazoles The related oxazoles: testing is ongoing. So far MYOS00527 was the only hit. Results to be uploaded.

Series 6: ketoximes Latest compound shipment OpenSourceMycetoma/Series-6-Ketoximes#5 https://github.com/OpenSourceMycetoma/Series-6-Ketoximes/issues/5, to be tested by @MA-Jjingyi https://github.com/MA-Jjingyi. Marij screened the first barch. So far we have 5 hits for which the IC50 will be determined. Results to be uploaded

Series 3: Tricyclics/Phenothiazines

-

OpenSourceMycetoma/Series-3-Phenothiazines#6 https://github.com/OpenSourceMycetoma/Series-3-Phenothiazines/issues/6

Kinase inhibitor library. The KCGS library was screened by Mickey. Additional drugs of similar classes were sent by @bebi78 https://github.com/bebi78 and screened by Marij. In total 6 drugs from the KCGS appeared to be hits along with one from the package sent by @bebi78 https://github.com/bebi78.

Bioinformatics

  • Did anyone hear from Waleed? @wwjvdsande https://github.com/wwjvdsande to check if he is still interested. To clarify means of contact in the meeting.

Misc updates:

Next Meeting November 27, 2023: chair: USyd; minute taker: UCL

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fantasy121 commented 11 months ago

Hi everyone, I can’t attend today meeting. I’ll be an apology for today.

wwjvdsande commented 11 months ago

@OpenSourceMycetoma/corecontrib I will make the new agenda and roster. I did it the last time too. is not much work. See you all in a minute

wwjvdsande commented 11 months ago

It seems that option D in the timing was not the optimal choice. We tentatively settled for the odd months on: New York 4:00, London 8:00, Europe 9:00, Sydney 19:00 (european wintertime) and New York 3:00, London 8:00, Europe 9:00, Sydney 17:00 (european summertime).

If there are objections to this. Please let me know. I will make the new roster early next week so you have till Sunday to let the objections known.

lferrins commented 11 months ago

Hi all, I won't be able to participate at those times (looks like 4 or 3 am for me), but I will keep updated on the GitHub and watch the recordings of the meetings.

lferrins commented 11 months ago

@MFernflower I just checked the masterlist and there are 15 compounds there from Northeastern, not 14. I also cross-checked them with those that were shipped and everything is fine. So I am not sure what the issue is that you are seeing.

MFernflower commented 11 months ago

@lferrins the compound in question is MYOS_00635_00_00 it has no smiles or neu id

On Tue, Nov 28, 2023, 9:10 AM Lori Ferrins @.***> wrote:

@MFernflower https://github.com/MFernflower I just checked the masterlist and there are 15 compounds there from Northeastern, not 14. I also cross-checked them with those that were shipped and everything is fine. So I am not sure what the issue is that you are seeing.

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lferrins commented 11 months ago

@MFernflower yes I see that - but all of the compounds that I have sent are accounted for in the masterlist. This row can be removed - unless there is another compound from a different lab that needs a number?

MFernflower commented 11 months ago

OK I will remove MYOS_00635_00_00 from the list

On Tue, Nov 28, 2023, 1:14 PM Lori Ferrins @.***> wrote:

@MFernflower https://github.com/MFernflower yes I see that - but all of the compounds that I have sent are accounted for in the masterlist. This row can be removed - unless there is another compound from a different lab that needs a number?

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MFernflower commented 11 months ago

I assume small paper about the latest mmv box will be published? @wwjvdsande

MMV1804559 looks nasty to synthesize - thoughts @mattodd

On Tue, Nov 28, 2023, 1:14 PM Lori Ferrins @.***> wrote:

@MFernflower https://github.com/MFernflower yes I see that - but all of the compounds that I have sent are accounted for in the masterlist. This row can be removed - unless there is another compound from a different lab that needs a number?

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MFernflower commented 11 months ago

@KlementineJBS can you reach out to @JuliaSarju through like email or phonecall?

I have not got update on any projects from York

wwjvdsande commented 11 months ago

I assume small paper about the latest mmv box will be published? @wwjvdsande MMV1804559 looks nasty to synthesize - thoughts @mattodd

Yes, @MA-Jjingyi is preparing a paper on the results of the COVID response box and the Pandemic Response Box. These data were not published yet but our aim is to do so.

wwjvdsande commented 11 months ago

@OpenSourceMycetoma/corecontrib I updated the spreadsheet with the data of all compounds screened by @marijschippers. IC50s are ongoing and will be added when the data is in.

KlementineJBS commented 11 months ago

@KlementineJBS can you reach out to @JuliaSarju through like email or phonecall?

I have not got update on any projects from York

I've just sent her an email, hopefully she'll get back to us soon

dmitrij176 commented 11 months ago

@wwjvdsande, thanks for uploading the latest bio assay data to the Master List. Recently, I had a closer look at the potency results and would be very grateful if you could clarify several things for me.

  1. With regards to in vitro results for Ketoxime Series 6, a lot of tested ketoximes show complete fungal growth inhibition at both 25 and 100 micromollar concentrations. These mentioned molecules have % growth values that fall below 20% which as has been previosly defined in MycetOS project is complete inhibition. Of course, we would expect for these structures to proceed to the next in vivo phase with preliminary IC50/90 and MIC calculations. But my confusion comes with the in vitro results analysis and writing. For instance, how do I define which analogues are more potent if they have similar values of less than 20% (or negative) ? For example, 19% and -4.8% are the same- potent and fully inhibitory.
  2. Is your team planning to do additional calculations (IC, MIC) and in vivo? If yes, then may I ask what would be the approximate timeline?
  3. Ive noticed that some non active compounds have derived fungal % growth values above 100% (like 125%). Is there a reason/explanation for that? Isnt 100% supposed to be the highest possible growth value as in any standard mathematical definition? Thank you in advance
wwjvdsande commented 11 months ago

@dmitrij176 The assay we run is a growth inhibition assay which means there can be some variation between experiments. A growth percentage between 19% and -4.8% does not mean much. It could be of some background noise in the fungal inoculum (if it melanized a lot in the original culture or not) or that there is a slight difference in inoculum size. That is of course a bit variable although we standardize it as much as possible, there can always be a difference of a few 100 cells per inoculum. So to answer your questions

  1. All values <20% are treated equal, we do them in triplicate and you can see the standard devation too. From that you can already note that there is always variation between the triplicates. Sometimes it can even be that around the minimal inhibitory concentration you see growth in one replicate and not in the other replicate. That is inherent on the assay and is seen in every microbe ever tested. So you might see this as a digital output. Value below 20% --> no growth. Value above 20% growth
  2. @marijschippers is currently running the IC50/90s. From that you can make a ranking already. The most potent ones will then be tested further against other strains. In vivo testing will only be done if they are very potent and if I have enough manpower to do it. @MA-Jjingyi is finishing up her PhD like you and @marijschippers will have to learn the technique first.
  3. Indeed some compounds have higher growth values than the growth control. That can have three reasons. In most cases it is simply the difference in inoculum size. We add hyphal fragments. if in one well just a few hyphal fragments are added more and the fungus is not inhibited you can see that in the growth. That usually explains growth differences like 100 or 125%. A second reason could be that a compound actually promotes growth. If we would add extra nutrients the fungus would grow quicker. Some of these compounds might stimulate grwoth. The last reason might be the most difficult to understand, it is a phenomenon called paradoxal growth. That is when a fungus is exposed to a high concentration of a drug for which it is normally susceptible and than turns on a massive stress response. Because of this stress response the metabolism changes and the compound would not inhibit the growth as it normally does. A famous example of this is the respnse the echinocandins (caspofungin, anidulafungin and micafungin) have on Aspergillus species. If you use a similar assay as we do, you see the signal first go up, than go down, than go up again before it falls below the detection limit.
dmitrij176 commented 11 months ago

Thank you @wwjvdsande. Very important information.

KlementineJBS commented 11 months ago

@KlementineJBS can you reach out to @JuliaSarju through like email or phonecall?

I have not got update on any projects from York

Apparently Julia has had to take some time off, but her colleague Dr Peter Rayner will update the Github soon.

MFernflower commented 11 months ago

@KlementineJBS Hopefully before Christmas!!!

wwjvdsande commented 10 months ago

@dmitrij176 @fantasy121 @mattodd I updated the spreadsheet with the latest IC50 and IC90 data.

dmitrij176 commented 10 months ago

@dmitrij176 @fantasy121 @mattodd I updated the spreadsheet with the latest IC50 and IC90 data.

Thank you Wendy. Has anyone received the last ketoxime package in Rotterdam?

wwjvdsande commented 10 months ago

@dmitrij176 yes we received it. We will start screening it after the Christmas break

mattodd commented 10 months ago

For insertion into the fenarimol the paper and perhaps for future discussion: results of DNDi/Eisai clinical trial of fosravuconazole. https://dndi.org/press-releases/2023/worlds-first-clinical-trial-for-mycetoma-shows-efficacy-new-promising-treatment/

MFernflower commented 10 months ago

@mattodd may also be worth talking about in ketoxime paper since same mechanism of action

(Series 1 and 6 hit cyp51 just like the DNDI azole)

On Sun, Dec 31, 2023, 9:11 AM Mat Todd @.***> wrote:

For insertion into the fenarimol the paper and perhaps for future discussion: results of DNDi/Eisai clinical trial of fosravuconazole.

https://dndi.org/press-releases/2023/worlds-first-clinical-trial-for-mycetoma-shows-efficacy-new-promising-treatment/

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