OSM Online Project Meetings

 

Date: Tuesday 16th August

Time: 1 hour meeting

Follow up to Meeting of May 24th 2016.

Agenda being assembled here.

To join, click here.

File: Slide Deck v2

File: Slide Deck v1

File: SDF of compounds suggested by Neil Norcross from The University of Dundee. Rationale/analysis here.

Update: Meeting recording. Follow-up planned here.

The next meeting will be hosted by Mark Gardner from AMG Consultants on May 24th. The link for registration is here (needed to get the link to join). Discussion can happen below or over on GHI386. The meeting will be part webinar, describing the project in outline briefly as well as ways for people to play with the data, and then some key issues facing the team will be outlined. These issues will be described ahead of the meeting.

Download: Slide deck for the webinar.

Download: Pre-meeting slide deck giving more information on the issues to be presented.

Download: The Series 4 Compound SDF (as of May 18th 2016)

This can be generated on the fly at Cheminfo.

Download: Slides from Chris Swain on how to interact with OSM's data

Follow-up OSM meeting that will gather and digest community inputs during and since the previous meeting. Click here to join. Wednesday 8th June at the same times of day as first meeting (8am East Coast US, Brazil, 1pm UK, 2pm CET, SAST, 10pm Sydney).

Initial flyer advertising the first meeting:

Meeting recording. Slide decks are attached. One used is v8.

Slides 2–5 (2:00 to 7:00). Potency measurements on the various batches of new Series 4 analogs.

July 2014: OK potency, poor cLogP. Around this time hERG data had led to a deprioritisation of the amide sub-series in favor of the ether sub-series.
Nov 2014: ca. 200 nM potencies with OK cLogP values. Pyridine analogs found to be non-potent.
May 2015: Edinburgh data. Triazolopyridines not potent.
June 2015: Better cLogP values and bolder structural changes, but unfortunately not potent.

Chris Swain asked whether reverse amides were made. No, though there was a reverse sulfonamide (MMV669103) and a transposed reverse amide MMV672990.

Slides 6–9 (7:00 to 23:00). Analysis of Metabolic Stability/ID Data (Master Post on known data) (wiki section)

Generally: the in vitro data for several analogs are not good enough, but are not too bad.

Slide 6: Experimental data suggests oxygenation is occurring, but it is not clear where on the molecules.

Slides 7–9: Implication is that use of blocking groups, e.g. in the benzylic position, is not helping a great deal. It is not predicted by either the aldehyde oxidase data or Chris Swain's predictive modeling that the TP ring is a problem. So what is the problem? Perhaps improvements in the gross parameters of the molecules should be the priority?

David Shackleford (Monash) (Audio level low): O-dealkylation could be the real problem. If the ether series are cleaved where indicated on slide 6, either of the two fragments could itself be oxygenated (i.e. a secondary metabolite). A possible test would therefore be to screen the two fragments, derived synthetically.

If O-dealkylation is a problem, then blocking groups next to the oxygen would become a synthetic priority. This could be included anyway as a strategy. Leading to: Next analog set planning: GHIxxx.

Paul Willis: Before doing detailed analysis on fragments, we should establish whether the in vitro data are well correlated with, and hence predictive of, in vivo data (i.e. an IVIVC). David: Let's check the existing data, and are any data missing? We could take compounds with low, medium and high in vitro stability into in vivo to check this correlation. Action: GHI351.

Chat activity relevant to this section:

Chris Southan: Do you do LC/MS for these experiments? (Ans: can check raw data files linked here)
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Chris Swain: Remember O-dealkylation would leave Oxygen on triazolopyridine ring: N1C=C(N(C(=N2)C(=CC=C3C)C=C3)C(C=1)=N2)O . Structures in GHI334. (Ans: No, the cleavage is the other side of the oxygen atom)
===
Paul MMV: Chris Have you run the full set of compounds through your predictive Clint programme / doe sit get the rank order right, how validated is it to use in target prioritisation.  Also does it look at species differences, in some cases cpds look better in man  

Chris Swain: I've only looked at representative compounds, and the program only predicts potential sites of metabolism not rates.

Paul MMV: OK I got confused by the slides and thought some of the the EH were predictions

David Shackleford: Paul - I suspect that the EH values are predicted from the Monash experimental CLint values (Ans: Yes, these are predicted based on experimental values)
===

Actions: Mat Todd to share all data with David Shackleford and evaluate whether we have in vitro-in vivo correlation. If not, should we submit low-medium-high clearance rate compounds to start to generate an IVIVC. Could later submit the O-dealkylation fragments for follow-up analysis to see if the oxygenated products derive from them. Done: GHI351.

Slide 10 (23:30-26:45) LogD vs. clearance data. No obvious trends: GHI333.

David Shackleford: important to consider logD vs. Volume of Distribution (VoD). Clearance impacts oral bioavailability, but VoD impacts on half life. For any compound where we have in vivo PK, particularly after IV administration, we should be looking at both clearance and VoD in the context of the physchem parameters, whether measured or in silico. We should try to get VoD data (measured/predicted) for compounds for which we have in vivo data. It would be useful if the calculated VoD values were predictive of the measured values - that would save a lot of time. GHIXXX.

It would also be interesting to see how well the measured solubilities (logD) are predicted by common software (cLogP): Done: GHI333.

Slide 11 (27:16-29:00) Can we modify triazole in MMV639565? Both imidazole compounds MMV669846 and MMV670250 have been examined. Tianyi Zheng was due to resynthesise the imidazole system in MMV669846, but the project ultimately turned more towards trying to find new synthetic methods for functionalising the triazolopyrazone core through bromination. Imidazole analog remains of possible interest, particularly if the C-H is substituted.

Slide 12 (29:00-29:45) Pyrazine modifications. Poorly tolerant to substitution. The northwest 6-position has not been explored. Tolerance there would permit an attachment point for pulldown experiments.

Slides 13-15 (29:45-34:12 with temporary SNAFU in period 33:00-34:00 where video froze and may be skipped)) Possible/residual targets suggested by the community.

Action: resolve GHIXXX (purchase from CRO) either way.

Slides 17-25 (34:12-46:44) Outline by Willem van Hoorn of approach used by Ex Scientia to predict new analogs worthy of synthesis, recently applied to Series 4.

Contrast between whether we want an exploitative approach (highest model scores, closest to known actives) or an explorative approach (go after chemical space that has not been well explored, meaning one expects fewer actives but there is likely to be more novelty). Matched molecular pair analysis can be deployed. Willem wondered whether you can use data from all the series?

Action: Re-run the analysis now that we have more data in the Master Sheet. GHIXXX.

===

Chris Southan: Willem - any 3D aspects in the modeling ?

Willem van Hoorn: No it's all based on 'flat molecule' fingerprints

===

Slide 26 (46:50-47:32) Suggested composite structures from Mrinal Kundu.

Slide 27 (47:33-48:34) Suggested alpha-CF₃ amine as isostere for amide, from Chris Burns. Lit sources: 1, 2. Would be a good project for someone to try. Isostere may remove problem of amide side chain in Series 4 which is electron withdrawing, potentially making compounds better substrates for aldehyde oxidase. Write up as synthetic branch? GHIXXX.

Slide 28 (48:35-53:55): Debrief on data management by Chris Swain. The Google Master Sheet of molecules now allows parallel entry by anyone, and downloading of the whole dataset. Use of Luc Patiny's Cheminfo to view molecules. Can also use proprietary software Vortex to view the molecules. Chris wrote an iPython notebook to allow similar viewing with open source tool, using RDKit to calculate properties. These approaches use the live dataset on the fly, which is part of the power.

Slide 37 (54:00, actually starts 55:44 ends 58:45): Chris Southan. Compounds are imported into Pubchem when a deposition is made to ChEMBL, but that leaves out the molecules in the project that have not yet been so deposited. If we are to capture the data more continuously into Pubchem, how do we do that? We also need to be careful of the number of synonyms each molecule possesses: how? Separate data management meeting to discuss: Action: Assemble agenda/time for this: GHI XXX.

(57:00): Action: Devise initial list of compounds for next stage of synthesis, then potential follow-up meeting: Existing locations for this: Post and GHI301. Now: GHIXXX.

 

The full content of the chat window is contained in the attached file.

Original links:

Times

Location

Agenda

Post authored by Mat Todd

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.

Context: OSM 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.

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 experiments. Action 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 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 experiments. Action 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

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 Item. Associated 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:

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