DNDi Open Synthesis Network

[bendndi]

The first two participating institutions from the DNDi Open Synthesis Network have recieved the preliminary data for the MycetOS project and ahole to initiate work over the Summer:

Illinois Mathematics ans Science Academy (IMSA) https://www.imsa.edu/site_section/discover/ Augusta University https://www.augusta.edu/

Hopefully representatives from both locations will join in on our Github discussions soon!

[bendndi]

The key files, including the OSN wanted list, can be found in the Files section of Series-1-Fenarimols: https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/blob/master/OSN_P4_Master%20target%20list%2020190418.sdf https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/blob/master/OSN%20P4%20Mycetos%20full%20data%20set%2020190417.sdf

[johnimsa]

I’m John Thurmond, a faculty member at the Illinois Mathematics and Science Academy (IMSA), and have been speaking with Ben from DNDi about joining this project. IMSA students will start with the syntheses of compounds P4_A_001, P4_A_003, P4_A_006, P4_B_003, and P4_B_004 from the OSN P4 Master target list.

[mattodd]

This is great! Welcome on board @johnimsa ! As an open source project, it'd be very good if your students were able to host their work publicly on a lab notebook so that the community can see what's going on. Is that possible? You have probably discussed all this with Ben. Can you briefly describe how you might go about working? Do you think your students will be happy to engage in conversations here on this platform so that we can all be connected?

@bendndi I downloaded the sdf but Chemdraw won't open it. Do you get the same error? If yes, perhaps you have to zip the file before upload? I don't know. Also, the target list: are you able to describe how the targets were derived? If that (and/or the structures) could be put somewhere (e.g. here or here) then we'd be sure we're not duplicating. I know it all takes time... Over in OSM we tried tagging Issues that describe active syntheses with the label "Being Synthesised Now" to try to allow easy collation of molecules under active investigation, but the system only works as well as the people maintaining the tags!

[johnimsa]

Thank you for the welcome @mattodd , we're very excited about being part of the community. The structures of the compounds we are going to synthesize are P4_A_001, P4_A_003, P4_A_006, P4_B_003, and P4_B_004. We opened the sdf file with DataWarrior. We're starting with the hydroxy intermediate provided by Ben to prepare these few target compounds to get familiar with the chemistry and we'll be following lab notebook procedures posted in this project. We'll then be able to prepare more compounds in the future (fall semester). We will be able to host our work publicly in some form of lab notebook to share our procedures and data.

starting intermediate

P4_A_001
P4_A_003
P4_A_006
P4_B_003
P4_B_004

[bendndi]

@mattodd Thanks for pointing out the issue with the sdf files, I saw the same problem. This confirms what I'd seen earlier which is that Github does not support sd as a format..

I was however able to get around this by uploading as a zip file here

If you can check if that works for you, that would be great. The three main files are in there, the OSN master target list (molecules I came up with and which I pulled from some of the suggestions on MycetOS e.g. from @MFernflower) plus the data sets in sdf format for use in designing molecules.

[bendndi]

@mattodd here is an image of the OSN target list, with IMSA selected compounds highlighted

[MFernflower]

@bendndi this is AMAZING! however I'd recommend you remove the compound with the N-Si (E.G the one without the methyl spacer) bond because of stability concerns

[MFernflower]

@bendndi What is the process of depositing compounds into this database?

[MFernflower]

@johnimsa please spin this off to a new ghi when you have time

[bendndi]

@johnimsa please spin this off to a new ghi when you have time

@MFernflower I'm not sure what you mean by this, can you please clarify :-)

[bendndi]

@bendndi this is AMAZING! however I'd recommend you remove the compound with the N-Si (E.G the one without the methyl spacer) bond because of stability concerns

Will do

[bendndi]

@bendndi What is the process of depositing compounds into this database?

@MFernflower just send me ideas or post ideas on here and I will add them in the the master list. Whenever the master list is updated (i.e. new ideas, successful completon of synthesis, or new assigning of compounds to synthetic teams,) I update it and swap the new version in for the old! The master sd list contains a column which records the source of the original idea.

[bendndi]

it'd be very good if your students were able to host their work publicly on a lab notebook

@mattodd do you have a specific lab note book you could recommend to @johnimsa ? The DNDi Open Synthesis Netowrk don't require any kind of specific lab notebook use, w ejust run with the expectation that at the time anything gets written up for publication each participant can provide the necessary experimental details.

Alos one other thing I was wondering about... IMSA have NMR and FTIR capabilities but no Mass spec capabilities. Do you have MS (or bettr still LCMS) capabiliites at UCL, and if so could we perhaps set up an arrangment where IMSA send samples to UCL for LCMS, and you them send them on to Wendy for test?

[MFernflower]

IR spec and NMR should be good enough to confirm if team made the product yes? @bendndi

On Tue, Apr 30, 2019, 1:30 PM bendndi notifications@github.com wrote:

it'd be very good if your students were able to host their work publicly on a lab notebook

@mattodd https://github.com/mattodd do you have a specific lab note book you could recommend to @johnimsa https://github.com/johnimsa ? The DNDi Open Synthesis Netowrk don't require any kind of specific lab notebook use, w ejust run with the expectation that at the time anything gets written up for publication each participant can provide the necessary experimental details.

Alos one other thing I was wondering about... IMSA have NMR and FTIR capabilities but no Mass spec capabilities. Do you have MS (or bettr still LCMS) capabiliites at UCL, and if so could we perhaps set up an arrangment where IMSA send samples to UCL for LCMS, and you them send them on to Wendy for test?

— You are receiving this because you were mentioned. Reply to this email directly, view it on GitHub https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/13#issuecomment-488042581, or mute the thread https://github.com/notifications/unsubscribe-auth/AAYEWDQMSZXXDW443DBQZ4LPTB62LANCNFSM4HG46CSQ .

[bendndi]

IR spec and NMR should be good enough to confirm if team made the product yes?

@MFernflower Not really... in my experience / opinion MS is pretty much essential. MS + 1HNMR as a minimum at all places I've worked. IR and NMR are entireley qualitative and open to interpretation, MS has an irrefutable quantitative element.

[MFernflower]

One last thing - I had a csv list of molecules I proposed - I feel if you merge that with your masterlist we would get a nice backlog of compounds for teams allover the world to dig into

https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/blob/master/Analog%20Planning/mfernflower/proposed_mols_datawarrior.csv

I checked and there are a few analogues from that csv that did not migrate into the OSN @bendndi

[mattodd]

Hi @johnimsa great, looks good. Everyone: it'd help the community to have these structures tagged as "being synthesized now". Over in Open Source Malaria we experimented with this by having a Github issue for each such molecule carrying a tag saying just that. That works where students can take charge of their molecule and post updates and plans to the issue as a form of diary, which remains open during the synthesis attempt. An alternative is to insert the molecules into the MycetOS Google Sheet Master List of compounds and tag them there as "being synthesized" which could involve the inclusion of a web link back here. A lengthier way is to post them to a "Desirable Compounds Not Yet Synthesised" page of the wiki, which installs them as "desirable and in progress" (here's the one for OSM Series 4). Any preferences? This is what @MFernflower is talking about when he mentions starting a new "ghi" (=Git Hub Issue) but I think we could usefully think about how we want to do this first. It will impact others we hope to work with here ping @alintheopen

@bendndi when I unzip your zip file on a Mac I get an odd file extension "OSN_P4 MycetOS 20190429.zip.cpgz" which, when I rename to .sdf does not open properly. Help @drc007?

@bendndi the image you posted of the targets seems to have that functionality of tagging something as "ongoing" plus a person responsible. What's the software?

@bendndi Lab notebooks. An ongoing, annoying issue. Labarchives has a free trial version which might do. Other solutions require some kind of inputs (cost or running a server, e.g. CDD, chemotion). The SGC guys use Zenodo as a way to deposit Word and PDF files. I don't like it as a solution since it doesn't work like a lab notebook with respect to raw data like spectra and images. Interestingly Github itself can be used as a public file store, which would work, but it's non-trivial. We need to fix this together by getting some money together for software development!

@bendndi @johnimsa Yes we can run LCMS in my lab of samples. If they become numerous we may need to think about cost, but we can certainly get started and see if it works.

@bendndi reopening this issue, by the way, I think you closed it by accident. I'm going to alert the community to your lovely pic above of the current targets ping @dmitrij176

[MFernflower]

@mattodd

Re the cpgz file:

"MacOS method of unzipping a zip file is to first create a new file with the zip.cpgz extension before actually returning the contents of the ZIP archive. It then opens this CPGZ archive and re-creates the ZIP file again, then decompress it gives back into zip.cpgz file... and this goes on infinitely.

This may happen when macOS doesn't understand the type of ZIP compression used with the file, so it thinks that you want to compress the file instead of decompressing it. Since CPGZ is the default format used for compression, which is Compressed UNIX CPIO Archive file, the file is just being compressed and decompressed over and over again.

The solution is to use a third party tool such as PeaZip or 7zip"

[drc007]

@mattodd the file is actually a folder containing three files, I've emailed them to you.

[MedChemProf]

I have a couple of new students beginning in the lab in a few weeks. Is the process to contributing compounds to the MycetOS project just picking targets on the Master Target List that are labeled as 'Not Started' and then making them in the lab? @bendndi

[MFernflower]

@bendndi @MedChemProf I believe the OSN masterfile is due for an update

[bendndi]

@MedChemProf Yep, the process is simply picking compounds from the master list which are "Not started", posting the sleection on here (so that I can update the list to reflect that you're owrking on them), and then cracking on with the synthesis. Note that I can provide some intermediate if needed, see elsewhere on this project

@MFernflower I'll update the master list once I'm back in the office later next week.

[bendndi]

The Synthetic Schemes for elaboration of the DNDi intermediate to make componuds on the OSN list can be found HERE and HERE

NOTE: Entry HPD11-1 is the alcohol-halogen exchange in the first lab notebook - AMS

Just check the tabs on the left hand side of the page to see the lab notebook pages of the students from the Todd lab in Sydney who pioneered these synthetic routes

[AndyBishopSevenoaks]

Thanks for getting us involved @mattodd we have a group of students ready to get stuck into this come the new academic year. How would we be able to obtain some intermediate to work from?

[MFernflower]

^ Paging @bendndi

[bendndi]

@AndyBishopSevenoaks I'd be happy to send on some of the intermediate, I just need the shipping details and your email address - you can either post these here or send on to me at bperry@dndi.org

[bendndi]

I've updated the OSN target list to include the compounds from @MFernflower . This can be found as an sdf here

(Note from mfernflower: the organosilicon compound is duplicated)

Here is the current target list as an image:

[MFernflower]

@AndyBishopSevenoaks what compounds from the list do you see your students making?

[bendndi]

I've updated the OSN master list for MycetOS to take into account the activites of @luxsika , and also to add in the logDs for the proposed moleucles for comarison with the logD's used in the original mycetos paper (using same lodG calculation method from Stardrop / optibrium.

[bendndi]

Out of interest, does anyone know if i'ts possible to "pin / sticky" a comment to the top of a forum / issue chat? Would be ideal to have the up to date image of OSN list at the top of this page... @mattodd

[MFernflower]

@bendndi I dont seem to notice any changes in the graphic above? Also I dont think github supports stickies just yet

[bendndi]

@MFernflower the image includes logDs calculated by stardrop, and the compounds selected by UCL have been flagged as such.

[MFernflower]

Please disregard the comments I made yesterday as I managed to mix up the UCL and imsa groups

[dmitrij176]

Good day @bendndi. I have chosen 3 compounds from the OSN master list to be synthesised. These are P4_C_001, P4_C_002, P4_C_003.

[luxsika]

Hi @bendndi

Previously, I mentioned that I was going synthesize P4_A_002, P4_A_005 and P4_B_010. Two of the reagents will only arrive in mid July, so in the meantime, I will be synthesizing P4_A_005 , P4_B_001, P4_C_009.

Hopefully I will be able to synthesize the initial compounds, but I will keep updating here. Sorry for any inconvenience.

Luxsika

[MFernflower]

@luxsika Link to your lab notebook?

[MFernflower]

@luxsika if you plan to go via the 4-piperidone route for the alcoholic compound you can also knock another compound off the list!

[MFernflower]

@dmitrij176 @luxsika This lab notebook will be of help https://au-mynotebook.labarchives.com/share/Matthew%2520O'Dowd%2520Hons/MC4wfDM2MzA4LzAvVHJlZU5vZGUvNDEyNjE5MjE2fDAuMA==

I would recommend you go a slightly different route for the halogenation - SOBr2 in DMF + DCM springs to mind

I wish you both the best of luck with your reactions!

[dmitrij176]

Project update

@bendndi @mattodd @MFernflower, I am currently working on 6 compounds that will be finished and fully characterised in early August. P4_C_001, P4_C_002, P4_C_003 are from the OSN master list (they appear under 2 codes in the scheme). DM8-DM10 are novel structures. logD calculations have been performed using ChemAxon at pH 7. For data consistency, @bendndi could you please recalculate logD values with StarDrop (unfortunately, I dont have access to it). Indeed, it appears that there is a certain degree of discrepancy in the generated results.

SMILES for the related structures:

DM6-1/ P4_C_001 : Fc1cc(Cl)ccc1C(c1cccnc1)N1CCOCC1

DM7-1/ P4_C_003 : Fc1cc(Cl)ccc1C(c1cccnc1)N1CCCCC1

DM8-1 : COCCN(CCOC)C(c1cccnc1)c1ccc(Cl)cc1F

DM9-1 : CC(C)(C)c1ccc(N(c2ccc(C(C)(C)C)cc2)C(c2cccnc2)c2ccc(Cl)cc2F)cc1

DM10-1: Fc1cc(Cl)ccc1C(c1cccnc1)N1CCc2ccccc2C1

DM11-1/ P4_C_002 : Fc1cc(Cl)ccc1C(c1cccnc1)N1CCC(F)(F)CC1

Synthesis update.zip

[MFernflower]

Compounds 8 and 9 should give interesting test results

Compound 9 remnds me of terbinafine and compound 8 reminds me of diphenhydramine (Both compounds show antifungal/antiprotist activity)

[luxsika]

Hi all! I just wanted to give a quick update of my research. I have synthesized and purified 5 compounds from the OSN master. They will be shipped off soon for biological evaluation. I may synthesis one more compound, depending on time as I am only in the lab till End of july/Mid august. My MSc thesis will be due on August 30th, so full characterization be done by then.

These are the compounds that I have made. @bendndi @MFernflower Would you be able to update the OSN master list please?

Also, I am bit confused. In terms of the OSN master list, how was it generated? and why were these modifications proposed? Would someone be able to send me any papers relating to this? Will be great for my thesis.

Thank you Luxsika

[MFernflower]

@luxsika some structural explanations can be found here: https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/blob/master/Theses%20Reports%20Docs/Hung%20Duong%20Hons%20Thesis/Thesis%20Presentation%20HPD2017%20v7.pptx

[MFernflower]

Great work everyone! This is more a note to me and @bendndi but need to update the open synthesis network image so I can re-edit the wiki

[bendndi]

@MFernflower @luxsika @dmitrij176 Updated OSN target with new status / new ideas

[bendndi]

@dmitrij176 let me know once your compounds are completed and ready for test and I'll update again.

[bendndi]

@dmitrij176 re LogD differences - this is perfectly normal, all LogD algorithms generate logD differently and are known to not necessarily corrlate well. The important thing is to make sure always compare using the same algorithm.

Note the question as to which logP / logD calculation is best has been tackled over and over again by many; the general consensus is that on a global level no one method is better than another, although at the more granular (i.e. chemical series) level you may find one calculation method predicts better than others when comparing to experimental. However, we currently don't have an experimental logD against which to benchmark the various methods...

[bendndi]

@luxsika Some pointers on the OSN target list

The OSN master list, at least the DNDi designed target components, are simply a diversity scan of different options around the core, focused mainly on the amino substituent. This is a (the?) classic approach to early hit-to-lead chemistry, particularly in the phenotypic space or when no structural info on the target is available. We're not designing each compound to answer a specific question, they are designed as a whole to anser the question -What is tolerated, and does anything give us a suprising jump in potency / efficacy? If after 50 or 100 compounds investigated in this way we don't find anything that gives us a big (~10x) jump in potency -i.e. if all compounds have about the same potency (flat SAR) or only the hit has potency and the rest are inactive - I'd probably start asking serious questions about if the series has any future potential.

So, the P4A-xxx compounds are scanning the piperazine nitrogen with "what about alkyl?, what about Urea?, what about amide?, what about benzyl..."_

The P4B-xxx are a bit more focused - "we known N-Ph is accepable off the piperazine, so now lets mess with the electronics and the steric space around that ring and see what happens"_

P4C-xxx are a bit more broad again - "piperazine is good, so what about morpholine? piperidines?, homopiperazine..."_

P4_D-xxx are compounds more closely related to the fenarimol parent molecule

Once a project moves further into the Lead optimization space it will become a more focused design-led process, but for now the empirical (scatter-gun) approach is essential.

[MFernflower]

@bendndi when you get a chance can you remove the duplicate firewalker (organosilicon) compound?

[fantasy121]

Hi All, I have officially stated my PhD and the University of Sydney so I will be more actively contributing to this project over the next few years. I want to claim compounds P4_D_MXF004, P4_D_MXF005, P4_D_MXF006 and P4_D_MXF009 as part of my synthesis for the coming months. In two days, I will make a more detailed post about all of the molecules I’m planning to synthesise in the early stage of my PhD that I think would be of interest.

[bendndi]

@fantasy121 Thakns for letting me know, here is the updated snapshot: