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26th March 2014 @ 02:46

Open Online Project Meeting of the Open Source Malaria Consortium (OSM)

Meeting took place - recording is here. Chat window text is captured in attached file (below). May be discussed i) in comments area below (log in via e.g. Google, or ii) on the GitHub pages corresponding to the various action items or iii) at this Google+ post.

Powerpoint used for screenshare is attached to this post, below.

OSM Mar 2014 Meeting Slides Latest.pptm

Action Items Posted After Meeting (for original agenda and actions, see later in this post):

1. Compound Synthesis

a) Jo Ubels to complete set of 6-8 compounds in the ether sub-series of Series 4. To Do: Post appeal for input of analog design - done: Which alcohols should the team buy to synthesise the next series 4 ethers?. Related to GH Issue 174. To Do: Post synthetic targets to GitHub along with timeline for completion. Example is GH Issue 165.

b) Tom Macdonald to complete set of 6-8 compounds in the amide sub-series of Series 4. To Do: Post appeal for input of analog design - done: Which Series Four Amines Should the Team Synthesise Next?. To Do: Post synthetic targets to GitHub along with timeline for completion. Related GH Issue: 168.

c) Tom Macdonald to complete synthesis of new batch of pyrazine carboxylic acid to validate that in-house synthesis preferred to commercial sourcing. Underway: Repeat synthesis of 3-(methoxycarbonyl)pyrazine 1-oxide (TM 4-3). Related GH Issues 164, 163.

d) Alice Williamson to complete synthesis of small collection of members of amide sub-series with variation in northeast portion of molecule. Underway, GH Issues 181, 180, 179, 178, 177, 176

e) Alice Williamson to synthesise racemic MMV669844, to validate that this side chain may be used/obtained. Enantiomers would be separated. This compound has replaced a previous analog with CHF2 in place of Me. GH Issue 166.

f) Alice Williamson to synthesise enantioenriched version of ether side chain. Underway: Synthesis of 3-(2-(Benzyloxy)acetyl)oxazolidin-2-one (AEW 129-1). Github Issue 167.

g) Patrick Thomson to secure copies of reports from Eduvie and Devon, which can be shared and their conclusions folded into the wiki section on synthesis.

h) Tom to work with Patrick on securing spectroscopic evidence for i) existence of hydrazone isomers and ii) their preferential reaction in the oxidative cyclization reactions. Related GH Issue 97. Action: Mat to set up GH Issue to collate evidence that can be fed into wiki (both lit and new exptl evidence).

i) Design and synthesize one trifluromethyl analog as a comparison with difluoromethyl analogs. Action ItemAssociated post. Open. Will follow successful synthesis of MMV669844, see above.

j) Series 3: i) Patrick is making two of the "twisted" compounds containing an o-methyl group: issue 161, and was asking about availability of OSM-S-139. Another twisted compound was planned: see Issue 118. Patrick to advise on which of these are synthetically active. ii) Carmen's summer project made progress with a number of compounds in Series 3, and has been summarised. Action: Mat to incorporate in wiki and to derive new Actions to cover synthesis of remaining compounds. Jimmy Cronshaw may be on hand to complete the synthetic work with Patrick.

2. Biology

a) Complete mechanism of metabolic clearance experiments. Action Item. Remains open. Status was checked in meeting - we wait for data at the moment.

b) To do before next meeting: chase data from Lawrence University compounds that were sent for evaluation.

3. Informatics

a) Mat Todd to set up a way for 5 compounds to be automatically imported into Chembl's open source malaria page, using e.g. sd file. To do: set up GH issue, then work with George Papadatos to make import happen.

b) A hERG assay was run on two compounds (hERG Data for MMV669844 and MMV670944) which were both positive (numbers were pIC50 = 5.6 and 5.2 while ideally we'd want compounds to be at about 4.5). This represents a warning flag, rather than a show-stopper - hERG is typically more of a problem with bases. Reducing this activity should be an aim of future analog design. Question: have any of the amides been evaluated in this assay? A: Yes, the two compounds evaluated are representative of the ether and amide sub-series. Future use of this assay: The assay employed in this case was a low-throughput patch-clamp assay, and it might be useful to run a higher-throughput competitive binding assay for future analogs. To do (MHT): Appeal for a collaborator to run this on a future round of Series 4 compounds. Done: GH Issue #192Informatics: It was suggested in the meeting by Sabin that it would be useful to compare these Series 4 compounds to any known hERG pharmacophore model(s). In the meeting, Murray volunteered to do this. Action: Mat to set up GH Issue: Done GH Issue 188.

4. Website

a) Action items to be constructed from OSM Web Design/Platform Meeting. To include some of the items below. Mat to do.

b) Daily digest funtion of Github issue 134 closed, has led to email summary service from Patrick Thomson that is now being evaluated for roll-out. GH Issue 162.

c) Mat to liaise with Coline Legrand to ask for what should be changed on the landing page or other sites. Open.

5. Other

a) How best can a CRO impact Series 4? Action Item.

b) Avoidance of duplication of effort (Action item) is a part of project tracking (Action Item) and the compliance of participants with that, which is the larger issue.

c) Newsletter. First newsletter complete (April 14th) and will be sent/posted. Hard copies may be used. Any OSM contributor should feel free to use this newsletter as a means of disseminating the project. To do: Alice to post updated powerpoint template to ELN. There is a residual problem that the URL hyperlinks are made inactive by conversion from ppt to pdf using Microsoft Powerpoint, requiring the use of Keynote, which in this first case required the re-insertion of all pictures. It would be useful to have a technical solution to this problem. To do: Mat to start GH Issue to ask for help.

d) OSM Paper 1 (pyrroles) - To Do: Mat and Alice to complete first draft and circulate to co-authors by end of April.

Date of next meeting: May 29th - Regular time (i.e. similar to the times for the current meeting)

End of Actions Arising

 

===Original text posted before the meeting is below this point===

Context: OSM is a drug discovery project operating along open source principles. There are bimonthly project update meetings. Anyone can participate, needing only a web browser. You can come along anonymously and spectators interested in how the project works are very welcome.

Meeting is at this online location and at these times. We will aim to have the meeting last no more than one hour.

The meeting will be recorded and the recording posted unedited on YouTube - participants are on the record.

For more background, those interested in attending may wish to view the most recent items on the To Do list, or those molecules currently being synthesised, or the wiki page for the current most-active series, Series 4.

Powerpoint File for Screenshare: 

OSM Mar 2014 Meeting Slides v1.pptm

AGENDA

Key items:

1.      Which compounds are currently being prepared – what are the timings for delivering the first compounds? How can we facilitate delivery? Focus on Series 4.

2.      Plans and timings to make website more user friendly - outcomes of web design meeting.

3.      Review of biological data and plans.

4.      MMV will shortly need an ESAC report – shall we complete this in an open source manner?

5.      Plans and timings for publications, particularly pyrrole series

Details, and responses to composite items from the Previous Meeting are shown below:

A - Actions arising

(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 ItemAppeal for help posted. Closed.

Background: MMV670652 was originally synthesised as a racemate. Promising activity. It was thought important to resynthesise this material as a racemate, then separate the enantiomers to investigate potency/metabolic clearance of each separately. The synthesis was a challenge owing to the need to introduce a difluoromethyl group. The very similar, and synthetically more accessible, compound (CHF2 vs. CH3) MMV669844 was known to be potent. In the original series documentation this latter compound was shown as a single enantiomer, raising the question of whether this compound had indeed been made and evaluated as a single enantiomer. Paul Willis looked into this, and reported (email) that MMV669844 was originally made in a steroselective manner, introducing the chiral center via a Sharpless, Jacobsen AD-Mix-B/tBuOH/H2O reaction on the styrene, but we do not have data on the ee of the final product. There is therefore an assumption that the compound is enantioenriched. Nevertheless, the immediate target of the synthesis of a Series 4 analog with a stereocentre in this position has shifted from MMV670652 to MMV669844. (Latest ELN entry to date dealing with synthesis of -OCH3 sidechain.)

Closing Issues referring to synthesis of MMV670652, though links preserved here in case difluoromethylation is required in future: 119, 115, appeal for synthetic help.

2) Separate enantiomers of MMV670652. Action ItemOriginal Action Item. Closed. See previous item. MMV670652 seen as less important immediate target than MMV669844. Closing relevant issues, though they may be needed in future should separation of enantiomers of MMV669844 be needed later: 111, 120,  

--> New action item to be posted, Synthesis of racemic MMV669844 (methyl analog of MMV670652).

For new results towards an enantioselective synthesis of this compound class, see Chemistry update below.

3) Complete synthesis of key pyridine carboxylic acid. Action Item. Summary of progress is currently on the wiki. This molecule can be, and has now been, made in several ways. Closed. Closing relevant issue 121, and 146 but data for the attempts needs to be collated (open issue on this 164), and data are lacking for experiments from OSM contributor Eduvie. Tom is looking into a decision on the best way to source this compound going forward (open Issue 163), i.e. a comparison of routes. He could use input from Patrick and Sabin on this.

4) Complete synthesis of one amide in Series 4. Action Item. Closing this older action item (122), but newer action item (152) remains Open. See chemistry summary for details. Tom is close to completing this now, e.g. here, giving complex NMR data but promising MS data. Alice is making alternative amides, see issues 157, 156, 155. Devon has been attempting much of this chemistry - we need ELN entries finishing, and a copy of final report? Patrick has suggested isomers of hydrazone important to the efficiency of the oxidative cyclisation (Issue 97)

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. Summary of all the analysis of which amines to use is contained in the wiki here. Closed.

6) Complete mechanism of metabolic clearance experiments. Action Item. Remains open. Updated quantities noted in the link. Status should be checked in meeting.

7) Design and synthesize one trifluromethyl analog as a comparison with difluoromethyl analogs. Action ItemAssociated post. Open. Will follow successful synthesis of MMV669844, see above.

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 as a good project, but relevant links are within the wiki so this item is Closed for now.

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. Closed. This phone call between Mat Todd, Alice Williamson and George Papadatos took place on Jan 22nd 2014. Upshot: George happy to scrape data from SD file that would populate the new open drug discovery page in Chembl with a table of data of the newest compounds, to allow browsing the data but these data would not be part of the Chembl database proper. During Chembl's periodic import of data into the full Chembl database, such data would then be included. This would be a good stopgap measure to allow visualisation of the newest compounds. It would also be possible to include a link for each compound to the relevant compound's summary page in the "Experimental Procedures" part of the lab notebook. Action: Start new Issue that trials this functionality, requiring there to be an update of e.g. 5 new compounds which can then be imported automatically.

10) Define three new functionalities required in Mike Robins' visualization tool. Action Item. Link to Mike's demo needed Scaffold Hunter generating images like this one, which will be a useful way to generate additional value on top of known data. Such images can be generated on the fly from the SD file. Hence issue 128 is being closed. Previous issues on visualisation 112 and 99 already closed. Section on visualisation added to wiki page on Technical Operations.

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. Done - relevant post and installed on wiki. Closed Issue 129.

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. Done and installed on wiki, hence closing Issue 130.

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. Closed. Done: post. Meeting took place Feb 17th/18th. Separate action items will be detailed below.

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. Relevant issue (132) closed. Design issues of web page remain open, below.

15) Can we tweak the "About" text on the landing page? Action Item 133. The text was altered by Chuck from Cloudcity here. Question remains can we change it? Answer from Chuck Fitzpatrick - Yes (i.e. text is available already), but need to know what you're doing. Closed.

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. Closed. There was some offline discussion that perhaps Coline Legrand (MMV) could assist with i) assessing what was most needed on the landing page and ii) writing parts of the wiki. New Action: Mat to forward details and sample tasks to Coline to see if this would work, due April 9th.

19) Avoidance of duplication of effort (Action item) is a part of project tracking (Action Item) and the compliance of participants with that, which is the larger issue.

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. Open and still assigned to Chris. Closed - discussed in meeting, and Chris' analysis posted here.

T - Chemistry - Any updates to chemistry issues not covered in the Actions Arising.
 - Alice enantioselective approaches to MMV669844
 - Jo has successfully completed an oxidative cyclisation to give the triazolopyrazine core and is now coupling this compound with alcohols (see this entry and issue 165). (Action item 158 closed)
 - Series 3: Patrick is making one of the "twisted" compounds containing an o-methyl group: issue 161, and was asking about availability of OSM-S-139. Another twisted compound was planned: see Issue 118. Patrick to advise on which are active.
 - Series 3: Carmen's summer project made progress with a number of compounds in Series 3, and has been summarised. Action: Mat to incorporate in wiki and to derive new Actions to cover remaining compounds. Jimmy Cronshaw may be on hand to complete the synthetic work with Patrick.
 - Murray offered to help in prioritising molecules to be made (issue 154)

U - Biology - Any updates to biology issues not covered in the Actions Arising
 
- Lawrence University compounds (Series 1) were sent for biological evaluation in the US and we're awaiting data.

V - Data - Any updates to data or data management not covered in the Actions Arising
 
- A new system for compound registration has been developed for OSM, using one page per compound. The compound structures are shown on one page. Clicking the structure goes through to a single page that lists all the attempts at the synthesis of that molecule, associated biological/analytical data, synonyms and strings. This change makes linkage between synthetic attempts far easier. The pages are maintained via one ELN account. A guide was written about how to create and maintain these pages. The system has been used by others, including Alice, Carmen, Inga and Jimmy - the relevant issue (148) about roadtesting the system has been closed. These pages will be useful in conjunction with ChEMBL's visualization system mentioned above. Likely in future that there will need to be a tutorial on how to add compounds to the SD file, including links to the OSM compound pages.
 
W - Wiki/website - Any updates to wiki and website issues not covered in the Actions Arising.
- There was some work done on the Series 4 wiki by Debra, who is no longer contributing. We need more assistance with wiki maintenance. Following the website consultation Stephanie Geerlings suggested (email) we be more explicit at the top of the wiki pages that they may be edited by anyone. A short section has been included in the wiki to link to compounds being made and the most recent to do items. Other action items arising from the Web Consultation Meeting in February:

i) Mat Todd to start Issue relating to whether Github items could be grouped by tag. Open. Related issue (141) - can we group all items related to a person?

ii) Mat Todd to start Issue on whether image previews from Github items could be generated on the landing page. Open.

iii) Mat Todd to suggest MMV project manager acts as Curator between primary content and what appears on the Landing Page, i.e. to direct the development of that site. Open.

iv) Mat Todd to start Issue on connecting OSM with people at Github to resolve Daily Digest email issue. Note - another way around this was suggested on Twitter, using the new site solvers.io. Open.

v) Mat Todd to make clear on the Wiki that the site can be edited by anyone. Open.

vi) Mat Todd to connect with Steph offline to see whether Google+ identity issue can be resolved for osdd.malaria account. Open.

vii) Mat Todd to set a date for an OSM email newsletter to incorporate latest developments/posts/data/requests. Open. See also below.

Other - Q - Do we want to change the "About" text on the landing page? This is possible (Issue 133)

Timeline for completion: end April

 
X - OSM Newsletter - How and who? Originally discussed in Issue 134 (closed) and now in Issue 159. Alice and Mat are working on a sample newsletter, which will be sent round via email and other platforms as a pdf. Deadline: Friday April 4th. The next newsletter will be sent out by Alice. Following that, the newsletters should be sent by other consortium members. Template (blank ppt file) will be posted to ELN.
 
Y - Dates of Future Meetings in 2014

- May 29th - Regular time (i.e. similar to the times for the current meeting)
- July 24/25th - 6 am Sydney (Fri 25th), 1:30 am New Delhi, 10 pm Geneva (Thurs 23rd), 9 pm London (Thurs 23rd), 1 pm California (Thurs 23rd) ("Alternative")
- Sept 25th - Regular time
- Nov 27th - Alternative time
 
To avoid daylight saving time confusions, exact times will be circulated/advertised nearer the time.
 
Z - Any Other Business

- Publicity - any suggestions for spreading word of project and project needs to a) scientists and b) non-scientists. Such moves can be discussed but need to be federated - i.e. contributors to OSM should feel free to reach out to people to obtain project help or publicity.

 

(this post authored by Mat Todd) 

Linked Posts
Attached Files
OSM Mar 2014 Meeting Slides v1.pptm
OSM Mar 2014 Meeting Slides Latest.pptm
OSM Meeting March 27 2014.txt