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23rd May 2013 @ 01:13

Open Online Meeting of the Open Source Drug Discovery for Malaria Project

N.B. Action items are currently live on GitHub:

When: Monday May 13th
San Francisco 11 pm (Sunday 12th)
New York 2 am
London 7 am
Geneva 8 am
New Delhi 11:30 am
Sydney 4 pm
Who: Anyone
Particularly who: med chemists and people with experience with using Github for science research.

A) Actions arising from meeting on Feb 26th:
B) Consideration of new data from arylpyrrole series
C) Consideration of new data and action items from aminothienopyrimidine series:
D) Construction of Top 10 for next round (if applicable)

Recording of the Meeting:

Posted on YouTube:

Chat During Meeting:

Meeting Chat 130513.txt

Minutes of the Meeting: (AEW)

Present: Matthew H Todd (MHT), Paul Willis MMV (PW), Alice E Williamson (AEW), Murray N Robertson (MNR), Althea Tsang (AT), Gaby (G), Greta Schmitt (GS), Peter Murray-Rust (PMR).

Apologies: Matin Dean (MD), Patrick Thomson (PT)

A) Actions arising from meeting on Feb 26th:

1. The aryl pyrrole sulfonamide was synthesised by PT and some other analogs which were biologically evaluated in Dundee and found to be inactive - this supports the data that indicates replacement of the ester is difficult and leads to reduced activities. This is the last analog from series one that was planned but MNR expressed his interest in the sulfonate which MD is in the process of synthesising. MHT agrees that we can pursue this compound whilst finishing off writing the paper on Series 1.

2. MNR has reduced OSM-S-109 to the amine and sent the compound for testing . MNR was confident with compound purity before sent for testing but doesn't have full characterisation data owing to solubility problems and so the compound will need to be resynthesised for data collection, there is plenty of OSM-S-109 precursor in the lab.
3. MHT has not yet contacted Sue Charman to test metabolic data for the methoxy-substituted near neighbor compound (OSM-S-111). This needs to be done prior to in vivo evaluation with Swiss TPH has an available slot for this to be evaluated in vivo. How much do we have Check available stocks of this compound (thought to be 30 mg)
4. AEW is still working on the experimental section of the paper and also needs to write a summary for the reasons for the "stops" on the arylpyrrole and the near neighbor set.
5. AT has synthesised 70 mg of OSM-S-106, MHT will contact Sue Charman to be asked about possibility of basic metabolic stability/solubility and also ask Vicky Avery about the possibility of late stage gametocyte assays.
6. Short consultation on thienopyrimidine derivatives performed by MHT and MNR and some have already been tested. 
7. Summary of Suzuki reactions trialled to date has been posted but no consultation required as AT got the Suzuki reaction to work under microwave conditions. 
8. Chlorothienopyrimidine found by MNR to be commercially available for a reasonable price (less than 1/5 of original quote), so at the moment involvement of CRO sector doesn't seem to be necessary - might revisit this if we need larger quantities, or in the future for the right molecule. Synthetic route is of course posted on the ELN.
9. MNR has been active with Knime and has been bringing AEW up to speed.
10. MHT is in discussion with developers about cost of setting up a project landing page/website.
11. Github has been shown to be quite effective for project management. Early days but AEW, MNR, MHT have found GitHub very useful for assigning tasks and general organisation. Already, the GitHub pages have received input from someone outside of the Todd group. MNR - not keen to have another website but GitHub seems to be the best online management tool, free and open with huge user base.
The team would like to pool jobs and get them to appear on Twitter feeds/RSS feeds. MHT questioned PW about the use of project management tools in pharma. PW says the tools are used more commonly in drug development rather than drug discovery but says we should experiment with GitHub. PW also questioned whether another 'login' would be a deterrent for the use of GitHub. MHT agrees, login required for comment but not to view data but proposes that we continue to trial GitHub for the next fortnight and appraise at next meeting - should eventually contain everything. MHT mentions SciGit (specifically designed for scientific project management) that is in beta, but currently GitHub is meeting our requirements.
12. Recontact Roche attendee from previous meeting - was done but no response received, might have been the wrong contact details but will investigate prior to next meeting along with other suitable med chem people.
13. Last meeting recording has been posted by MHT
14. Team of 49 undergraduates at Lawrence University (USA) have been synthesising some near-neighbour compounds. Near-neighbour compounds not currently being pursued by OSDD team but chemistry straightforward and suitable for UG class. MHT has been assured that the data will be posted when they can. Data not currently posted in public domain, but if the experiment works then suitable near-neighbours will be tested and evaluated.
15. MHT still needs to re-contact Mike Pollastri for possible involvement.
16. PT keen to switch to synthetic chemistry input on thienopyrimidine series, other potential sources will be explored following discussion on which thienopyrimidines to synthesise next.
B) Consideration of new data from arylpyrrole series
  • Sulfonamide made by PT is inactive, sulfonate might be of value currently being synthesised by Matin - these represent final two compounds from this series.
  • No synthetic effort going into arylpyrroles/near-negihbours at the moment - checking solubility of a couple of compounds with Sue Charman but everything else is being written up for submission of a paper. 

C) Consideration of new data and action items from aminothienopyrimidine series:

  • Four picture files summarise biological data received from Vicky Avery's lab, some issues with solubility have been flagged.
  • SAR data quite diffcult to see, although data is clear.
  • Background: Aminothienopyrimidine with attached aryl sulfonamide (TCMDC-135294) was in the original TCAMS data set and found to have potency of 150 nM. This compound was resynthesised (OSM-S-106) and high potency confirmed as 36 nM. Jimmy Cronshaw performed survey of commercially available aminothienopyrimidines (most lack aryl group) which were bought and tested. Most had low or no activity. Synthesis around the core has involved changing the amino group to a morpholine ring, a pyrazine (deduced from another active TCAMS compound TCMDC-132385). The aryl ring has been modified according to commercially available boronic acids/esters - many were para substituted. Essentially all changes have killed activity. CLogP were evaluated prior to synthesis but even so, some solubilities were surprisingly low. OSM-S-106 seems to have a very tight SAR and few patterns have been deduced from the data. Currently, reconsidering the hit compound OSM-S-106 and seeing if we have overlooked some simple substitutions that we could evaluate. Need low logP compounds and diversity in synthesis. 
  • MNR expresses his and AEW's view that there could be two modes of action in play. The compounds that extend from the amine vs those that do not (e.g TCMDC-132385 vs OSM-137 without sulfonamide sees little change in activity whereas OSM-S-123 vs OSM-S-106 shows dramatic difference in potency). MNR suggests that modifying amino group or extending from sulfonamide should be explored independently.
  • MHT asks if we should resynthesise TCMDC-132385 to check potency. MNR and AEW agree that AEW should resynthesise.
  • MHT questions PW about his opinion on the data. PW suggests two phases: 1. Profile OSM-S-106 - measured solubility, microsomal stability and profile through the life stages so we understand strengths and weaknessed of the lead to put series into context. Contact Sue Charman for phys chem and in vitro DMPK. 2. Overall, SAR does look quite tight but many changes seem to have been led by synthetic accessibility and are a little speculative (e.g. amine replaced with aryl ring). Points to specific interactions from lead, need to know if this is a singleton or a potential series with scope for further optimisation. PW suggests range of targets that vary substituents on sulfonamide and amino group (acyclic, secondary and tertiary, then extended to amino ethyl or hydroxy ethyl to boost solubility and maybe find another interaction). Also 1 or 2 ortho substituents on phenyl ring to force the molecule to twist - exisiting molecules could be too planar leading to stacking and insolubility. 
  • MHT likes ortho ideas and also shares the idea from Sydney team regarding di-meta subsituted aryl compounds.
  • PW thinks we should focus on less speculative, incremental changes on amino and sulfonamide substituents to make sure that this series is a viable target for optimisation.
  • MHT suggests that we select 10 or so compounds featuring obvious changes for the next round of testing and make decision on series after this. PW agrees but thinks that some of the Chemistry may be quite difficult so important to get some of the key boronic acids - asks if we have done searches and if we need to reach out to some of the companies and ask for donations?
  • AEW asks if the team should do some changes on the core. PW says no. If the core is altered, the substituents will still need to be modified for optimisation so it makes sense to address this first as changing the core probably won't drive the project forward. MHT explains that the Sydney team discussed simple changes in the heterocyle (e.g furan rather than thiophene) if chemistry was straightforward and functionalisation similar. Team have currently done searches on a number of different cores, their synthetic accessibility and commercial compounds. MHT suggests we might have a go at the synthesis of some new cores IF they are easy to access. PW suggests researching any new cores within the TCAMS set to influence the teams decision. MHT explains that this has already been done and ChEMBL is returning no hits.

D) Construction of Top 10 for next round (if applicable)

  • MHT suggests that this list be published online ASAP. PW will send his suggestions and then proposes a deadline of 1 week to publish suggested compounds online and then another week for open consultation before the final 10 are selected two weeks from now.
  • PW suggests that we think of the best way to widely publicise the targets proposed.
  • RSC have told MHT that they will distribute/publicise the list.


  • PW says he will liase with AEW for testing of OSM-S-106 against liver stage activity/gametocyte activity to profile life cycle activity. MHT to contact Sue Charman for other asasays.
  • PW suggests the team starts to identify other series in case the aminothienopyrimides aren't a viable solution. MHT highlights a new wiki page constructed by AEW for this purpose. The team will continue to look at some other series. MHT suggests we clear with GSK those series that aren't being investigated by others. PW agrees to liase with GSK and other groups and advise the team to prevent duplication. AEW asks if we should consult with PW prior to posting data on the wiki. PW says its fine to post on the wiki but to send him the link as soon as the data is posted.
  • Next meeting planned for July, dialogue continues on G+ and GitHub. GitHub contains details of action items that can be performed outside of the lab, MHT encourages people to have a look at have a go with GitHub.

Action Items:

Aminothienopyrimidine Series

1. Post suggested aminothienopyrimidine targets for the next round of synthesis and evaluation (MHT/AEW) along with appeal for assistance.

2. Contact the RSC to ask them to circulate the data (MHT)

3. Analyse any input from the community and select the next ten compounds for synthesis (MHT/PW/AEW)

4. Embark on synthesis (AEW/PT and anyone who wants to participate!)

5. Identify new sources for synthetic input (MHT/PW/AEW)

6. Send OSM-S-106 for life cycle profiling (AEW)

7. Search for suitable ortho-substituted aryl boronic acids. Identify and order compounds needed (AEW/PT) and if required request donations from commercial sources (MHT/PW)

8. Resynthesise TCMDC 132385 to confirm potency (AEW)

9. Contact Vicky Avery about possibility of running late stage gametocyte assay on OSM-S-106 (MHT)


10. Re-synthesise OSM-S-138 to collect data (AEW)

11. Continue writing experimental for the paper (AEW)

12. Finish draft of paper (MHT/AEW)

13. Contact Lawrence University UGs to ask them to post data online (MHT)

14. Contact Sue Charman regarding metabolic data for OSM-S-111 and OSM-S-106 (MHT)

Project Admin

15. Continue use of/familarisation with Knime (AEW/PT)

16. Get an OSDDMalaria website/landing page up and running (MHT)

17. Continue use of GitHub and appraise 2-3 weeks from now. If positive, roll-out across the OSDDMalaria team (MHT/AEW/PT and any other users)

18. Discuss new methods to promote the next online meeting/ OSDDMalaria work and contact some medicinal chemists directly to invite them to participate in the next meeting. (MHT/AEW)

19. Think about the best ways to publicise data and ask for assistance (MHT/AEW)

20. Contact Mike Pollastri for possible involvement (MHT)

21 Write minutes and post recording (AEW)

Next Series

22. Identify other potential series for the OSDDMalaria team to target (MHT/AEW/PT)

Attached Files
Meeting Chat 130513.txt