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15th November 2014 @ 23:30

Logistics: Meeting is virtual at this online location and at these times. Will last 1 hour max. The meeting will be recorded and the recording posted unedited on YouTube - participants are live and on the record.

ContextOSM is an "open source" drug discovery project. Anyone can participate in the meeting, needing only a web browser. You can view the meeting anonymously and spectators interested in how the project works are very welcome. For more background, browse 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 for Screenshare: Attached to this post, below, with incremental revision numbers.

OSM Nov 2014 Meeting Slides v3.ppt

Recording of Previous Meeting

Recording of this meeting (#9) (coming)

 

MINUTES posted following the meeting (original agenda remains below)

1. Recent Progress in Synthetic Chemistry

 1.1 Access to Core Ether and Amide Triazolopyrazines.

   1.1.1 Wiki has been updated with a summary of ether and amide core synthesis following Tom and Jo completions. Access to core pyrazine carboxylic acid - also summarized in the latter section. Related GHIs needing to be closed out: 164, 163. Done. Action: Tom and Jo Honours Theses need to be uploaded to the ELN "Shared Data" for completion (Mat To Do).

 1.2 Access to Halogenated Triazolopyrazine Core. Cyclizations to TP cores seem to be working, halogenations need repeats and further investigation. Suitable for wider community synthesis project. Wiki updated. To Do: Write up for community project.

 1.3 Access to Fluoroalkene Isostere and Aminocarbonylation Chemistry.

   Fluoroalkene: Wiki updated with most recent developments. To Do: Post as open community project.

   Aminocarbonylation: Most recent ELN entry and Github Issue (259) added to wiki section. To Do: summarise project for follow-up by community, and post Tom Macdonald thesis online.

 1.4 Separation of Enantiomers of Chiral Compounds.

  Open: Ethers: Wiki has been updated on the background. Open: Scale up synthesis of OSM-S-208 or OSM-S-265 (active: GHI 236) for separation of enantiomers, and find a group willing to do this separation. Possible solutions: GHI 111. Aliphatic side chain ether analogs also under investigation (GHI 238 and 239) though only known comparable aliphatic analog (MMV670762) is inactive.

  Open: Alcohol: Related synthesis of the alcohol: GHI 178. One rac analog being made (GHI 235) - related analogs MMV672723 and MMV672687 both potent.

  Open: Amines: Ongoing synthesis of rac-NMe2 analog: GHI 242 (similar to MMV670437 (44 nM)), rac-NHMe analog: GHI 241 (similar to MMV670763 (inactive)) and rac-NH2 analog: GHI 240 (similar to MMV671651 (279 nM)). These amines also listed as attractive targets in GHI 261. The inherited analogs are all shown as enantioenriched, but no ee data available.

 1.5 Enantioenriched version of ether side chain of e.g. MMV670652. Underway: Synthesis of 3-(2-(Benzyloxy)acetyl)oxazolidin-2-one (AEW 129-1). Github Issue 167. To Do: update in meeting.

 1.6 Edinburgh: Series 3: i) Patrick and Tom are making "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. Recent active issue from Tom: 268. (Background: 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. iii) Edinburgh Series 4: Jamie is making two interesting pyridine derivatives (GHI 266, 267). Edinburgh guys to summarise in meeting.

 1.7 New inputs from Sydney Grammar. Target: synthesis of chloro-functionalised intermediate suitable for further coupling. Relevant posts: New Molecules from our Local High School and Sydney Grammar School Join OSM

2. Most Recent Potency Evaluations

 2.1 Single Shot Potencies for Compounds Submitted to GSK in June 2014 was followed up by IC50 determinations on the actives in July: IC50 determination of Compounds Sent to GSK Done

 2.2 Most recent set of new Series 4 compounds were sent to Sygene in September: Samples sent for in vitro efficacy evaluation against Plasmodium falciparum asexual blood stage and results were obtained in October: Evaluation of Latest Series 4 Analogs in Ether and Amide Series Done

 2.3 Lawrence University Compounds were evaluated in September: Potency Data for Crowdsourced Lawrence University Compounds and written up on Mat's blog here. Done

  Action (Mat): new activity data (above) needs to be folded into wiki

3. Other Evaluations of OSM Compounds

 3.1 hERG: New data: Compounds sent for evaluation against the hERG ion channel at AstraZeneca To discuss in the meeting. Background on wiki, as well as the data obtained. Remaining: i) 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. Remains open. ii) Informatics: It was suggested (Sabin) that it would be useful to compare these Series 4 compounds to any known hERG pharmacophore model(s). GH Issue 188. Remains open.

 3.2 Aldehyde Oxidase: Debate about which compounds to send Which Compounds to Send for Aldehyde Oxidase Assay? was followed by Pfizer sending Results of Series 4 Aldehyde Oxidase Assay Data posted to wiki. Some comments from SCott Obach also posted to ELN entry above. Some Series 4 compounds are not substrates, meaning if metabolic clearance is a problem, that clearance may be by other means? Link to decision on compounds to send to Sue Charman: GHI 213, 260 (remains open) Comparison with other data from metabolic clearance reveals few obvious trends, but as discussed in the meeting the assays are distinct - i.e. microsome stability assays do not contain AO. Is it possible that the non-potent amide (MMV670246) is inactive because of AO clearance, or is there no AO in in vitro evaluations?

 3.3 "ATP4" assay on Series 1 and 3: Ion Regulation Assay for OSM Series 1 and 3 Inactive. To Do: make sure data linked to wikis for these two series.

 3.4 Several Series 4 compounds have been sent for evaluation against "ATP4 resistant mutants" in the Kirk and Fidock laboratories: Samples Sent for Evaluation Against PfATP4 Resistant Mutants No action needed in meeting. To Do: Chase and post data to ELN and wiki.

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

 3.6 Sustainability of these assays. To what extent can we rely on such assays in the future? Open question.

 3.7 Need to assess whether our cLogP predictions are accurate, by comparing known logD values with those predicted, and potentially securing more data on these. Mat To Do.

 

 

 

AGENDA for meeting #9

1. Recent Progress in Synthetic Chemistry

2. Most Recent Potency Evaluations

3. Other Evaluations of OSM Compounds

4. Planning of Next Molecules

5. Informatics

6. Publications

7. Publicity

8. AOB

9. Summary of Actions

10. Agreement on Date of Next Meeting

 

DETAILS of these agenda items, incorporating items from OSM Online Project Meeting 8 (3rd July 2014) are shown below:

 1. Recent Progress in Synthetic Chemistry

 1.1 Access to Core Ether and Amide Triazolopyrazines.

   1.1.1 Access to Core pyrazine carboxylic acid - better than buying? Related GHIs needing to be closed out: 164, 163.

 1.2 Access to Halogenated Triazolopyrazine Core

 1.3 Access to Fluoroalkene Isostere and Aminocarbonylation Chemistry

 1.4 Racemic MMV669844. (Racemate is assigned OSM-S-208) was made: GH Issue OSM-S-208 and compound is potent:Single Shot Potencies for Compounds Submitted to GSK Remaining: 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.

 1.5 Enantioenriched version of ether side chain of e.g. MMV670652. Underway: Synthesis of 3-(2-(Benzyloxy)acetyl)oxazolidin-2-one (AEW 129-1). Github Issue 167. To Do: update in meeting.

 1.6 Edinburgh: Series 3: i) Patrick and Tom are making "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. Recent active issue from Tom: 268. (Background: 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. iii) Edinburgh Series 4: Jamie is making two interesting pyridine derivatives (GHI 266, 267). Edinburgh guys to summarise in meeting.

 1.7 New inputs from Sydney Grammar. Target: synthesis of chloro-functionalised intermediate suitable for further coupling. Relevant posts: New Molecules from our Local High School and Sydney Grammar School Join OSM


2. Most Recent Potency Evaluations

 2.1 Single Shot Potencies for Compounds Submitted to GSK in June 2014 was followed up by IC50 determinations on the actives in July: IC50 determination of Compounds Sent to GSK

 2.2 Most recent set of new Series 4 compounds were sent to Sygene in September: Samples sent for in vitro efficacy evaluation against Plasmodium falciparum asexual blood stage and results were obtained in October: Evaluation of Latest Series 4 Analogs in Ether and Amide Series

 2.3 Lawrence University Compounds were evaluated in September: Potency Data for Crowdsourced Lawrence University Compounds and written up on Mat's blog here.


3. Other Evaluations of OSM Compounds

 3.1 hERG: New data: Compounds sent for evaluation against the hERG ion channel at AstraZeneca To discuss in the meeting. Background on wiki. Remaining: i) 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. Remains open. ii) Informatics: It was suggested (Sabin) that it would be useful to compare these Series 4 compounds to any known hERG pharmacophore model(s). GH Issue 188. Remains open.

 3.2 Aldehyde Oxidase: Debate about which compounds to send Which Compounds to Send for Aldehyde Oxidase Assay? was followed by Pfizer sending Results of Series 4 Aldehyde Oxidase Assay To discuss in the meeting, but clearly some Series 4 compounds are not substrates, meaning if metabolic clearance is a problem, that clearance may be by other means. Link to decision on compounds to send to Sue Charman: GHI 213, 260. Comparison with other data from metabolic clearance reveals few obvious trends. Perhaps the inactive amide is inactive because of AO clearance?

 3.3 (No action needed) "ATP4" assay on Series 1 and 3: Ion Regulation Assay for OSM Series 1 and 3 Inactive.

 3.4 (No action needed) Several Series 4 compounds have been sent for evaluation against "ATP4 resistant mutants" in the Kirk and Fidock laboratories: Samples Sent for Evaluation Against PfATP4 Resistant Mutants No action needed in meeting.

 3.5 (Not for meeting) Complete mechanism of metabolic clearance experimentsAction Item. Remains open. Status was checked in meeting - we wait for data at the moment.

 3.6 Sustainability of these assays. To what extent can we rely on such assays in the future?

 3.7 Need to assess whether our cLogP predictions are accurate, by comparing known logD values with those predicted, and potentially securing more data on these.

4. Planning of Next Molecules

 4.1 Main item for discussion: what needs to be made, and for what reason. Who will make?

  4.1.1 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.

The ESAC then reported back on OSM with useful advice:

ESAC Report 2014

  4.1.2. Best recent summary of thoughts about next molecules: Alice on GHI 261.

  4.1.3. Other legacy discussions of possible targets for browsing, in conjunction with the newly-updated SAR section of the wiki:

Which alcohols should the team buy to synthesise the next series 4 ethers?. Related to GH Issue 174.

and  Which Series Four Amines Should the Team Synthesise Next?.

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)

Specific issues:

i) CF3vs. CHF2 group: CF3 is effective replacement for CHF2 for the northeast, see section 1.2 in presentation. (Is GHI 181, still needed.active?) Of separate interest is whether CF3 can be used in northwest: Legacy Action ItemAssociated post. Open. Will follow successful synthesis of the racemate, see above. e.g.

OSM-S-208.

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


5. Informatics (Recommend: Defer to future focussed meeting)

 5.1 Data on ATP4/Malaria Box. Kiaran has published data on activity in ion homeostasis assay of the 400 compounds in the malaria box. Result: many diverse chemotypes are active. Need: pharmacophore model. Following meeting: Mat will collate data thus far and start open consultation on the model, and who might contribute.

 5.2 (Not for meeting) Automation. GH issue set up dealing with the need for more automation, i.e. automated import of data from the ELN into other resources: GHI 225. Action on this is ongoing, requiring a separate meeting. Other activity: Auto-import to chembl has not been solved yet. Related: (GHI 212). Some possible interest in this from Mozilla Science Lab,

 5.3 (Not for meeting) Compound Numbering. GHI 172.

 5.4 (Not for meeting) Data Management. 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.

 5.5 (If Chris comes and we've time) Chris Southan has kindly put up some cheminformatics issues that we ought to be aware of, such as duplications and communications between Chembl and Pubchem

6. Publications

 6.1 (Brief discussion) Main Series 1 Paper.

 6.2 Series 4 and Series 3 Papers.

7. Publicity

 7.1 (Brief mention) Sharing of Twitter Account. Anyone interested in sharing login/posting rights for @O_S_M on Twitter/Facebook etc?

 7.2 (Not for meeting) Action items remaining from OSM Web Design/Platform Meeting. To include some of the items below. Mat to do.

 7.3 (Not for meeting) Mat to liaise with Coline Legrand to ask for what should be changed on the landing page or other sites. Open.

 7.4 (Not for meeting) 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.

 7.5 (Brief mention) Newsletter. First newsletter was completed (April: OSM Newsletter #1). Alice posted the powerpoint template to ELN for others: OSM Newsletter Template. Appeal for help has been made (GHI 269) and Patrick has volunteered to assemble.

8. AOB

  8.1 (Brief Discussion) How best can a CRO impact Series 4? Action Item.

9. Summary of Actions

10. Agreement on Date of Next Meeting

 

(Not for meeting) Miscellaneous items on To Do List

All synthesis participants: continue to post synthetic targets to GitHub along with timeline for completion. Related GH Issue: 168. Targets synthesised need closing. The following GH Issues need resolving one way or another: 181, 180, 179, 178, 177, 176

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.

 

Post originally authored by Mat Todd

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Attached Files
OSM Nov 2014 Meeting Slides v1.ppt
OSM Nov 2014 Meeting Slides v2.ppt
OSM Nov 2014 Meeting Slides v3.ppt