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Open Online Project Meeting of Open Source Malaria (OSM)
Thursday 10th October 2013
6 pm Sydney
8 am London
9 am Geneva
12:30 pm Delhi
3 am New York
midnight in San Francisco
Mat Todd (MHT), Paul Willis (PW), Alice Williamson (AEW), Patrick Thomson (PT), Joie Garfunkle (JG), Devon Scott (DS), Eduvie O (EO), Egon Willighagen (EW), Elena (E), Ingra Topolnicki (IT), Kat Badiola (KB), Matthew Tarnowski (MT), Stefan Debbert (SD).
Action Items Arising from Meeting: See here
1. Series 3 (Aminothienopyrimidines)
AEW and PT responsible for synthesis of remaining aminothienopyrimidines (http://malaria.ourexperiment.org/uri/40a) PT will take care of 24 and 25 and AEW the other molecules. PW asked whether series 2 should be 'outsourced' to other groups/individuals with the core team focusing on Series 4. MHT mentions the importance of publishing this data and AEW the fact that synthesis could take place whilst waiting for Series 4 starting materials. Agree to continue with series 3 but to impose some time constraints on the synthesis.
2. Series 4 (New Triazolopyrazines)
a) MHT and AEW have drawn up a list of 9 proposed compounds (active and active) from series 1-3 to send to Kiaran Kirk. PW suggests that submission is limited to three compounds (e.g. 2 active and 1 inactive from series 1) as the assay is labour intensive and speculative at the moment. The team may also want to send more compounds from series 4.
b) AEW has started series 4 synthesis according to CRO data for MMV670652 (but using 4-bromobenzaldehyde in place of 4-formylbenzonitrile as the compound hadn't arrived). PIDA reaction proved lower yielding and requires optimisation. Cyanation reaction didn't work - most probably owing to problems with the cyanide reagents.
MHT flagged difficulty of obtaining Freon gas (as described in CRO synthesis) and questioned the importance of introducing difluoromethyl rather than, for example trifluromethyl. PW suggests trifluromethyl could be a good surrogate and that JG has been looking at the routes and ideas for the synthesis. JG's mentioned in the chat that the use of trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (and related compounds) for introduction of difluoromethyl groups.
MHT asks if we have any more synthetic data for the amides, AEW confirms that only experimental data for the synthesis of MMV670652 has been provided to date - this could be adapted for the synthesis of other ether linked structures.
c) MHT cites the briefing document (provided by MMV) as a very useful document to guide decisions about the next molecules to synthesise for series 4. The final paragraph of the document makes some suggestions (summarised here) and PW has recently sent over the structure of the 'missing amides' from the document. MHT highlights the promising features of this amide and suggests that resynthesis of this compound and other related amides. Related to this point is d) and e) MHT emphasises the need to see all of the data from the CRO in order to make the best decisions and not synthesising known inactives - some amides were inactive.
PW thinks amides are worth looking at but need to choose carefully as a number have been synthesised and were found to be inactive. PW mentions that getting all the data out in the open is currently representing an IT challenge but that he will try to get out an incomplete set of data so that project participants can at least see some SAR. JG has some suggestions for amides to target as the amides solved rat metabolic stability (more stable in vitro) and therefore are attractive but potency remains an issue.
MHT clarifies that with regards to the data, data extraction from the Word document is not necessary, the team just want to see all the data for any compounds that haven't been disclosed so that we can search on structure vs. potency and think about which molecules to target next.
MHT asks about 'item 3 on the briefing document', which mentions the synthesis of different heterocyclic cores. Should we be targeting different cores or just focus on the side chains for the first round? PW says this sounds sensible but suggests that if others have different cores in mind then they should work on synthetic routes for their synthesis so that the team can look at the feasibility of the synthesis.
JG has posted some suggested series 4 targets, including some amides and also the resynthesis of MMV670652 and separation of the enantiomers to evaluate their properties. PW emphasises the importance of resolving the two enantiomers to look more closely at difference in properties such as potency or metabolic stability. As the chiral synthesis looks tough we can perform a racemic synthesis and then resolution of the enantiomers - perhaps need to look for a collaboration.
d) MHT: Informatics guys are keen to receive the data – in whatever form (excel/sdf). Also need to think about the best way to share data. Currently all of the data is stored in an SD file instead of an excel sheet, which was less useful for informaticians. MHT asks EW if he would speak on behalf of the informatics team and asks if he would rather receive an SD or an excel file for example. EW: An Excel spreadsheet isn’t bad but an SD file represents the structures better than an Excel file as smiles aren’t as explicit as other mdl files, but this is being improved. EW also mentions a Syngenta plugin for Excel, which can actually show the structures (as drawings) - within the file. EW is not sure if this uses smiles or mdl mol file. MHT mentions a plugin from chemaxon (recently mentioned by CS) which enables users to view the structure and asks whether the plugin is required to just view the structure or just in order to create the Excel file. EW says not, no chemaxon just cdks (link to cheminformatics paper??).
MHT asks what we can do with the SD file to help people to browse data without necessarily installing software. EW suggest that with software bioclips could be useful but maybe not right now. Without installing software EW suggest open docs platform where you can upload an SD file and browse through it and even run toxicity predictions. MHT would like to see an instruction on the page for users to convert the SD file into a web browser - keep it simple. PW agrees that it would be better to have a platform that didn't require any software to be downloaded as this could act as a barrier to participation. EW thinks open docs might be the way forward. MHT would like to know if the SD file could be automated to update the opendocs platform daily/weekly. EW thinks this could be possible and will get back to the team - follow up discussion outside of the meeting.
PW on metabolism – are the metabolic flags for series 4 rat specific? We can’t fix a metabolic problem until we know what it is…want to get some metid information on the series 4 compounds. JG and PW to submit some series 4 compounds (that are already available within MMV) to the metid assay – a few mgs will suffice.
3) Clerical. MHT explains that currently he and AEW are doing most of the wiki updating and blog writing. As the project grows, keeping the project updated becomes more time consuming. MHT thinks we need to target retired chemists (RSC) or other networks of non-scientists and asks if anyone has any ideas for how to engage new team members to assist with the clerical tasks. PW agrees that this is very important and can be done by non-scientists so we need to reach out beyond our community.
MHT wants to pencil in the next meeting and calls for A.O.B. No other business but meeting proposed for 2 months time. PW keen for meeting in two months and also on following up the important action items from this meeting. MHT highlights the use of Github for the project and asks AEW to write a 'how to' for signing up to GitHub. PW would be happy to receive a 'how to' as hasn't found GitHub intuative and asks that we refer to series 4 as the 'triazolopyrazines' so that newcomers to the project will know what we're referring to. PW thanks those who have contributed in the chat window and MHT asks AEW to capture the chat as a txt file.
Thanks and close.
1. Series 3 (Aminothienopyrimidines)
a) Final selection of 10 compounds
Questions: who is assigned to make them, and by what date?
2. Series 4 (New Triazolopyrazines)
a) Which compounds to be sent to Kirk for ion regulation assays?
b) Initial compounds being made - OK?
Experimental work to date:http://malaria.ourexperiment.org/triazolopyrazine_se
Background to Series 4:http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series
c) Compounds to be made next - main item of business in this meeting
Relevant location of question:https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/86
Need for some informatics:https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/87
d) Need raw data from briefing document
e) Any other data needed on existing/known compounds, to further understand the series strengths/weaknesses?
3. Clerical - general help needed with writing of wiki and paper. How can we recruit?
a) Comments on usability of site(s) - whether scientists find it easy to get up to speed. Whether it is easy to navigate to the right information.