Open Online Project Meeting of Open Source Malaria (OSM)
Context: This post contains the agenda, recording, minutes and action items of an open project meeting of the Open Source Malaria (OSM) consortium. Much of the discussion pertains to the currently most-active compound series, Series 4.
Video - Recording is here.
A screenshare of a powerpoint file was trialled for this meeting:
Updated presentation file
Recording of the Meeting:
Chat Window Capture:
Minutes and Action Items from the Meeting:
1) The physicochem/metabolism work by the Charman lab (relevant closed GH issue) indicates that reasonably rapid clearance is observed for this series, and that this is not a mouse-specific issue. Solubility is also generally low. Both these issues need to be improved, and this is now the main focus of the OSM project on Series 4.
2) The metID work has suggested that the core heterocyclic ring is subjected to an oxidation (though we do not know the extent to which the compound is oxidized, only the presence of certain peaks), and the nature of the side chain apparently made little difference (i.e. this is probably not the way to stop turnover), meaning it is likely that amides made in this series in the near future will also suffer from this problem. Nevertheless the efficacy is seen as sufficiently promising that we can continue to pursue the amides as they are. i.e. they are sufficiently robust for this point in the project. The drive, within the amides, is to increase solubility without impacting (or ideally improving) potency.
Note that the compounds sent for both Charman studies were different (no overlap) but given that Charman does the sol/met studies for the metID compounds in any case this was not an issue. The choice of compounds was based on having a broad spread, and based on what was/is available.
The next stage of investigation of these compounds would be to establish the mechanism of the clearance (oxidation). Is it CYP-mediated? Does this tell us how to prevent it? Does this knowledge make the prevention strategy more predictable?
3) Synthesis of MMV670652. The etherification with the difluoromethyl group (on slide 7 of the ppt slide of the meeting), 23 to 24 remains a challenge. It would be good to have some community suggestions on this. Progress towards the synthesis of MMV670652 is ongoing. Enantiomers will be separated on completion.
4) Is the difluoromethyl substituting necessary? Not clear. Paul did a search during the meeting - it does not look like a trifluormethyl has been made, implying this is an interesting target.
5) Carbonylation chemistry is interesting, but will require work, making it risky. This is a very nice academic project for a lab to pursue, with a real application. The CRO guys did not appear to get it to work, (on slide 4 of the ppt slide of the meeting). Instead, the apparently safer route will be pursued that relies on the pyridine carboxylic acid and formation of the amide bond before oxidative cyclisation, (on slide 3 of the ppt slide of the meeting).
6) Chris Southan's analysis of public/commercial availability: there are no relevant compounds known, i.e. we are dealing with a novel set. This is very nice in one sense (basic medchem novelty) and implies we should seek to have these compounds screened more widely (is there mileage in having them included in MMV's Pathogen Box, for example). But does mean we need to make these compounds. Note that the search Chris carried out was against the full excel sheet of 118 compounds which contained the amides, even though these do not feature much in the blog post itself. An action item is to get these compounds into Chembl so that they are more easily searchable, and so that the data will filter through to Pubchem (amongst other things).
Subsequent to the meeting in discussions at MMV, the following relevant points came up:
1) Might it be a better idea for there to be no duplication of effort in synthesis - e.g. should there be multiple groups working towards the central Series 4 carboxylic acid? Might it be a better use of time and resources for some of the students to be actively pursuing new compounds, rather than intermediates? Perhaps students could make amines ready for coupling. On the other hand some of the chemistry is perfectly set up for undergraduate student projects, i.e. with an educational flavor and of suitable length. It would be useful, regardless, to be clear about who is doing what, coupled with approximate deadlines. We need to enforce this more strongly - that people have assigned (or self-assigned) tasks on Github with context and deadlines.
2) There don't seem to be many LCMS data in the ELN - any reason for this? All data ought ideally to go up there, but we tend to focus almost exclusively on NMR spectroscopy.
3) Also a reminder to everyone using the lab notebooks that:
i) Context as to why an experiment is being done is important - e.g. link to previous attempt, or a statement of the rationale.
ii) It's important to post all data
iii) It's very useful to show when a reaction is finished by writing, at the start of the entry, a conclusion when it is available. This makes browsing the ELN much faster.
4) It would be useful to know who is active on the project and what are they doing - i.e. an up to date list of people and how they are involved. There is no easy way to do this, I think? Is there a way of collating all the tasks assigned to someone? Otherwise we're going to have to rely more on mini blog posts/updates, and that's not likely to work.
5) Major issue: it's still a pain to get to the new/important info/data/activity on the website (where, and on which websites, for example, do we find out what's been happening on Series 4, and the latest, most important data). On the landing page there is a little box that reveals when you click "about" but this could be improved. What we'd like is to have little boxes that could be sorted according to Github label - What's new in Synthesis, What's new in biology, what's new in Series 4, etc. Can we do this somehow?
We need a project website design meeting in January and we need to ask people along who know/care about website/project design. We need to ask Cloudcity development along to this meeting.
Subsidiary question: can we edit that text in the About window on the landing page ourselves - i.e. do we have the access?
We also need to invite the RSC (David James) to that meeting, to discover what they are doing in the area of website design for collaborative science. MHT ought to try to see them in early Jan.
6) Github is generating too many emails for some people and is likely to be off-putting to those unused to working with this platform. Gmail collates these fairly painlessly, but other programs like Outlook do not, meaning there's a lot of apparent "spam". Is there a digest function for GitHub to limit the number of emails sent per day?
7) Data visualisation: Mike's pilot visualisation of project compounds is very good - data/fields can be added to the SD file and these will be reflected in the appearance of the compounds. In parallel with optimizing this we need to re-raise the issue with Chembl of whether we can do a periodic (daily) import from the central SD file. Is there a problem with this idea? Are Chembl interested in solving this, since this seems like a powerful approach for the future. Machine import of any and all data that people might want to post in this and other projects. Can we include links to further info on each compound (important in an open source project where there will always be more information about things).
8) It may be possible to get some CRO work done on synthesis in the new year. What can they do that is valuable and focussed?
9) It might be possible to secure some time to a Project Manager - what can they do that is maximally impactful? My suggestion is the improvement of the wiki and folding in new data/ideas as they come in. In particular a new section at the start of the page on what's new/being done right now.
(composite of this meeting and the previous):
1) Complete synthesis of racemic MMV670652 through solving difluoromethylation step. Post appeal for help from community on difluoromethylation, along with full context: what we know of the literature and the links to the attempts described in the ELN. Action Item. Appeal for help posted.
2) Separate enantiomers of MMV670652. Action Item. Original Action Item.
3) Complete synthesis of key pyridine carboxylic acid. Action Item.
4) Complete synthesis of one amide in Series 4. Action Item.
5) Design set of 5 amines for inclusion in first round of amide synthesis using the now-preferred pathway, with a view to increased predicted solubility. Action Item.
6) Complete mechanism of metabolic clearance experiments. Action Item.
7) Design and synthesize one trifluromethyl analog as a comparison with difluoromethyl analogs. Action Item. Associated post.
8) Post the carbonylation project as a self-contained project that a new partner may wish to pursue as a federated part of OSM. Action Item. Done. Posted. Could still use promotion.
9) Restart discussions with Chembl about automatic import of SD file. Action Item. This was addressed when Mat visited the EBI in early Jan 2014. TC due Jan 2014.
10) Define three new functionalities required in Mike Robins' visualization tool. Action Item. Link to Mike's demo needed.
11) Guidelines to people about how to use Github. Action Item. A how-to guide has already been written. The point of this action item is to make sure people are placing things in context and linking out.
12) Guidelines to people about how to post to the ELN. Action Item. How-to's have been written. Issue is also related to prople providing context to posts and ensuring proper use: Action Item. Need to write post that incorporates these common "extra" features of using ELN and Github.
13) Organise follow-up meeting in late January on website design, and post draft agenda with issues for people to consider. Invite RSC and Cloudcity. Action Item. Done: post.
14) Consider a section in the Series 4 wiki that spells out what is happening now and who is doing what, or some other way that is made clear to the outsider what the activity is. Action Item. Done on wiki page.
15) Can we tweak the "About" text on the landing page? Action Item. The text was altered by Chuck from Cloudcity here. Question remains can we change it?
16) Does Github have a daily digest function? Action Item.
17) How best can a CRO impact Series 4? Action Item.
18) How best can a Project Manager Impact Series 4? Action Item.
20) Chris Southan established the novelty of the series. There ought to be another quick check before the next meeting to see if the situation has changed given that two of the compounds are now submitted to PubChem and their properties will be computed. Action Item.
20th December 2013
Sydney 7 pm
London 8 am
Geneva 9 am
Delhi 1:30 pm
New York 3 am
San Francisco midnight
Meeting location: http://webconf.ucc.usyd.edu.au/osmdec20/
1) Actions Arising from the Previous Meeting (October 10th 2013)
(These were collated on Github)
Main issue remains ease of navigation for newcomers, and being able to drill down to current/recent activity. There is a serious issue here w.r.t. providing context and cross-links in all posts/inputs. There is also an issue w.r.t. keeping the wiki up to date. Suggest closing this Issue and opening new ones based on specific new action items.
Much discussion on this issue, also here.
Has led to Mike Robins' new visualisation directly from the OSM SD file: http://22.214.171.124:3000/
Comments on what's needed here?
Update on this part of the project (Alice).
Deadline for completion?
Suggestions for who will do resolution/separation?
Various possible approaches to be summarised in meeting (Alice).
Is synthesis with amide in place the way forward, or should we pursue carbonylation?
Not being pursued as yet. Cores already investigated (perhaps with suboptimal side chains) may be perused on wiki page.
Most recent syntheses shown in the Series 3 ELN - final Suzuki reactions being performed. Original consultation on this series in May 2013. Subsequent refinement of final compounds in September.
2) The Triazolopyrazines (Series 4)
a) Progress towards MMV670652 - Addressed above
b) Update from Patrick on Edinburgh compounds - slide in meeting, see also relevant Issue on oxidative cyclisation chemistry.
c) Update from Stefan progress towards the amides. Slide.
"There are a few different plans to the central acid. Will be two students spending ~10 hrs/week on it starting in January. If can get ca. 10 g of chloropyrazinecarboxylic acid, then bigger undergrad class can work on that project. It'd be three linear steps:
1) amidation of pyrazinecarboxylic acid / synthesis of arylhydrazone from aldehyde (splitting the class in half)
2) coupling the two halves (nucleophilic aromatic substitution)
3) cyclization to triazolopyridine (which will hopefully also be worked out by then)
If the acid synthesis proves intractable, or if the cyclization does, then could contribute in other ways."
d) Which compounds are we currently prioritising, and are these (still) correct?
e) Updated: Are there any known compounds related to this series in e.g. PubChem? The answer appears to be no: Chris Southan's blog post.
3) Other Series, residual issues
a) Completion of Series 3 - described above.
b) Compounds (arylpyrrole and aminothienopyrimidines, Series 1 and 3) have been sent to Kiaran Kirk for ion regulation assays for interest - no data yet, but if it arrives before the meeting then some discussion.
c) Compounds in the Series 1 Near Neighbour set have been synthesised by Stefan's students and need to be evaluated biologically. A lab has been identified willing to do this. Quick quality control needed on NMR spectra before submission.
4) Other recent biological data
a) Late Stage Gametocyte Assay on two compounds from previous series
5) Comments on GitHub and other data sharing/project tools.
6) Comments on ongoing requirements for improving the barrier to entry for medicinal chemists new to the project.