All Notebooks | Help | Support | About
9th June 2014 @ 12:35

ContextOSM 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. The meeting will also be streamed live into a room at the 2014 Australian Society of Parasitology Annual Conference - not part of the official program, but delegates will be able to view what is going on.

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.

Presentation File (PDF) for Screenshare: 

OSM July 2014 Meeting Slides v8.pdf

Recording of Meeting:

Chat window within meeting:

OSM Meeting Chat July 2014.txt


1. Review of most recent potency dataSingle Shot Potencies for Compounds Submitted to GSK

--> Planning of which compounds should be prioritised next:

See the newly-updated SAR section of the wiki.

Other previous suggestions: Github Issue 101, 123.

Current active issue on amides: 207.

Amide blog post: Which Series Four Amines Should the Team Synthesise Next?

Current active issue on ethers: 174.

and: New Directions for Series 4 (Joie's original suggestions)

2. Review of other biological data obtained or in process.


 PK/met ID

3. Update on plans and timings for publications in second half of 2014

 i) Series 1

 ii) Series 4 

4. Activity on website/platform/publicity/community development

 i) ChEMBL import - how do we automatically visualise SAR data?

5. AOB


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

Actions Arising from Previous Meeting

1. Compound Synthesis

a) Jo Ubels to complete set of 6-8 compounds in the ether sub-series of Series 4. Done: Five compounds submitted: Compounds Submitted for Testing at GSK Tres Cantos for anti-malarial and anti-TB activity.

Preliminary data obtained: Single Shot Potencies for Compounds Submitted to GSK

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. Done. To do: targets achieved need closing.

b) Tom Macdonald to complete set of 6-8 compounds in the amide sub-series of Series 4. Done: three compounds submitted: Compounds Submitted for Testing at GSK Tres Cantos for anti-malarial and anti-TB activity.

Preliminary data obtained: Single Shot Potencies for Compounds Submitted to GSK

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. To do: targets achieved need closing.

c) Tom Macdonald to complete synthesis of new batch of pyrazine carboxylic acid to validate that in-house synthesis preferred to commercial sourcing.

Complete? Resynthesis of 6-chloropyrazine-2-carboxylic acid (TM 10-3) To do: Close these 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. GH Issues 181, 180, 179, 178, 177, 176

Done: Two amides sent, along with chlorinated S/Ms (Preparation of OSM-S-219 and Preparation of OSM-S-220) as presumed negative controls: Compounds Submitted for Testing at GSK Tres Cantos for anti-malarial and anti-TB activity

Preliminary data obtained: Single Shot Potencies for Compounds Submitted to GSK

e) Alice Williamson to synthesise racemic MMV669844 (racemate is assigned OSM-S-208) to validate that this side chain may be used/obtained. Enantiomers would then be separated. This compound has replaced a previous analog with CHF2 in place of Me (MMV670652). GH Issue 166.


Compound appears potent:

Single Shot Potencies for Compounds Submitted to GSK

To Do: Scale up for separation of enantiomers, and find a group willing to do this separation. Possible solutions were discussed in GHI 111.

Related synthesis of the alcohol: GHI 178.

To Do: Decide on compound numbering for compounds thought, but not known, to be enantioenriched. OSM-S-208 is the racemate, and MMV669844 is the same structure but presumed to be enantioenriched. What code should be assigned to MMV669844? GHI 172.

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. To Do: update in meeting.

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. Done: Links on Github Issue 97. To do: Post copies of these reports somewhere permanent.

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. Trifluoromethyl groups being employed in northeast portion of molecule, e.g. GHI 181, but of more interest is in their use in ethers in northwest portion, i.e. as analog of:


as a means of assessing whether the difluoromethyl of super-potent MMV670652 is needed.

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. There is the possibility of an Edinburgh student completing more work on this Series (GHI 217)  ii) Carmen's summer project made progress with a number of compounds in Series 3, and has been summarised. Action: Mat to incorporate results in wiki and to derive final list of Actions to cover synthesis of remaining compounds. Item remains open.

2. Biology

a) Single shot data came in on several compounds from GSK, which will have been discussed above as main agenda item. IC50s on actives are pending.

Single Shot Potencies for Compounds Submitted to GSK

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

c) To do before next meeting: chase data from Lawrence University compounds that were sent for evaluation. Done. Waiting to hear.

d) Aldehyde Oxidase Assay. It's possible that the Series 4 compounds are being metabolised by aldehyde oxidase. Appeal was made for a collaborator to run Series 4 compounds through an appropriate assay. GHI 124. Chris Swain provided some suggestions, including paper from Pfizer, Groton. To Do: Mat to contact some labs.

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. Done: GHI 225. Action on this is ongoing.

Other activity: Auto-import to chembl has not been solved yet. The inherited MMV data are being incorporated into the next release of ChEMBL, scheduled for late July, via a manual import by George (GHI 212). The auto-import issue remains open. There is some possible interest in this from Mozilla Science Lab, tbc.

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.

Physical hERG assay: The assay employed above 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 #192. Pending.

Informatics: 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. Pending.

New Activity: An offer was received to screen several more compounds in a patch-clamp assay. There was discussion on which compounds to send (GHI 211) and a shortlist was drawn up for shipping:

Screening of hERG Activity in Series 4 Compounds

All herg activity can be seen here:

An up to date summary of where we stand is on the wiki.

c) Discussion on whether to give OSM codes to all intermediates (GHI 172). Answer: yes. Updated the How-To for the compound registration system:

How to Maintain the OSM Compound Numbering System

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. New deadline of July 11th for circulation of semi-complete draft.

e) MMV ESAC report was completed in May, and all files have now been posted:

Reports Submitted to MMV ESAC Meeting June 2014

The PDF of the appendix acts as a useful general summary of where OSM is up to as of May 2014.

Linked Posts
Attached Files