{"action":"created","issue":{"url":"https://api.github.com/repos/OpenSourceMalaria/OSM_To_Do_List/issues/358","labels_url":"https://api.github.com/repos/OpenSourceMalaria/OSM_To_Do_List/issues/358/labels{/name}","comments_url":"https://api.github.com/repos/OpenSourceMalaria/OSM_To_Do_List/issues/358/comments","events_url":"https://api.github.com/repos/OpenSourceMalaria/OSM_To_Do_List/issues/358/events","html_url":"https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/358","id":116314048,"number":358,"title":"OSM Series 4 - Next Round of Synthesis","user":{"login":"mattodd","id":4386101,"avatar_url":"https://avatars.githubusercontent.com/u/4386101?v=3","gravatar_id":"","url":"https://api.github.com/users/mattodd","html_url":"https://github.com/mattodd","followers_url":"https://api.github.com/users/mattodd/followers","following_url":"https://api.github.com/users/mattodd/following{/other_user}","gists_url":"https://api.github.com/users/mattodd/gists{/gist_id}","starred_url":"https://api.github.com/users/mattodd/starred{/owner}{/repo}","subscriptions_url":"https://api.github.com/users/mattodd/subscriptions","organizations_url":"https://api.github.com/users/mattodd/orgs","repos_url":"https://api.github.com/users/mattodd/repos","events_url":"https://api.github.com/users/mattodd/events{/privacy}","received_events_url":"https://api.github.com/users/mattodd/received_events","type":"User","site_admin":false},"labels":[{"url":"https://api.github.com/repos/OpenSourceMalaria/OSM_To_Do_List/labels/question","name":"question","color":"cc317c"},{"url":"https://api.github.com/repos/OpenSourceMalaria/OSM_To_Do_List/labels/Series%204","name":"Series 4","color":"8A0829"}],"state":"open","locked":false,"assignee":{"login":"mattodd","id":4386101,"avatar_url":"https://avatars.githubusercontent.com/u/4386101?v=3","gravatar_id":"","url":"https://api.github.com/users/mattodd","html_url":"https://github.com/mattodd","followers_url":"https://api.github.com/users/mattodd/followers","following_url":"https://api.github.com/users/mattodd/following{/other_user}","gists_url":"https://api.github.com/users/mattodd/gists{/gist_id}","starred_url":"https://api.github.com/users/mattodd/starred{/owner}{/repo}","subscriptions_url":"https://api.github.com/users/mattodd/subscriptions","organizations_url":"https://api.github.com/users/mattodd/orgs","repos_url":"https://api.github.com/users/mattodd/repos","events_url":"https://api.github.com/users/mattodd/events{/privacy}","received_events_url":"https://api.github.com/users/mattodd/received_events","type":"User","site_admin":false},"milestone":null,"comments":17,"created_at":"2015-11-11T11:26:51Z","updated_at":"2015-11-23T16:41:46Z","closed_at":null,"body":"**It’s decision time on the next set of targets.**\r\n\r\nAlice just mailed [the latest set of analogs she has shepherded through (OSM-S-291 to OSM-S-301)](http://malaria.ourexperiment.org/biological_data/13775). This set contains a few compounds that will add to the data surrounding tolerance in the northeast (arising from our 1st year undergrads and Seb Dath’s work ([1](http://malaria.ourexperiment.org/the_osm_blog/8904), [2](http://malaria.ourexperiment.org/the_osm_blog/9117)), and some compounds probing tolerance of a benzyl-linked pyridine in the northwest - we could still explore benzyl substituents more, particularly with blocking groups (as per Chris’s [suggestion](https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/301#issuecomment-112431903)) - see below for more on this.\r\n\r\nBut which molecules are next? Generally we need to lower predicted logP, work towards lowering metabolic clearance times while maintaining or improving potency.\r\n\r\nAnalog design in this series has previously been discussed: [June 2015 ELN post](http://malaria.ourexperiment.org/the_osm_blog/11565), [March 2015 ELN Post](http://malaria.ourexperiment.org/the_osm_blog/11545), [December 2014 Xmas Shortlist](http://malaria.ourexperiment.org/the_osm_blog/11379), and in issue #301. \r\n\r\nThe most recent biological evaluations were:\r\n[June 2015](http://malaria.ourexperiment.org/biological_data/11080)\r\n[May 2015 Edinburgh](http://malaria.ourexperiment.org/biological_data/11127)\r\n[November 2014](http://malaria.ourexperiment.org/biological_data/11216)\r\n[July 2014](http://malaria.ourexperiment.org/biological_data/10456)\r\nand the most recent online meeting was: [July 2015](http://malaria.ourexperiment.org/osddmalaria_meeting_/8194)\r\n\r\nSummarising the data, and all the many and various community suggestions to date (particularly from the [last meeting](http://malaria.ourexperiment.org/osddmalaria_meeting_/8194)), we can arrive at some guiding principles:\r\n\r\n1) **Benzylic blocking groups** have not to date resulted in significant improvements in metabolic stability, leading to the suggestion that improvements in gross parameters of the molecules should be improved, most notably logP. **cLogP for any proposed analog must now be below 3**. This rules out several interesting compounds (red crosses, below) that need to be redesigned, and places a question mark over marginal compounds (orange crosses). For example those [suggested](http://malaria.ourexperiment.org/the_osm_blog/11567/Series_4_Suggestions_from_Mrinal_Kundu.html) by @mrinalkundu would need to be modified with this design criterion in mind - the same goes for the [updated set from Mrinal](https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/301#issuecomment-123589279). We do still need to show better the correlation between measured and calculated solubilities, though. There is no clear trend between logD and metabolic stability, for the limited number of compounds we have measured (#333). Note that the cLogP values are only approximate and [are in Chemdraw sensitive to whether X-H bonds are drawn out explicitly](http://malaria.ourexperiment.org/the_osm_blog/11283).\r\n\r\n2) However, blocking groups next to oxygens in the northwest linker should be explored, based on the metabolic ID work discussed in the [last meeting](http://malaria.ourexperiment.org/osddmalaria_meeting_/8194), since it could be that **O-dealkylation** is occurring next to the TP ring. See also #334\r\n\r\n4) We should probably avoid unsubstituted pyridines, generally, though the Sydney Grammar samples below should be taken through to completion given that we have them!\r\n\r\n5) To generate an IVIVC, #351, it might be necessary to re-synthesize specific compounds, but we await input on this point from David Shackleford.\r\n\r\nThese considerations lead to three groups of compounds - the ones that ought to be made immediately, those that are highly desirable and those that are more speculatively interesting.\r\n\r\n## The Immediates\r\n![summary of immediates](https://cloud.githubusercontent.com/assets/4386101/11089993/6b4200ca-88c2-11e5-8011-a816df8ce376.png)\r\n\r\n**Nemesis**: Alice is in the process of making this, though it’s being a tough nut. \r\n\r\n**The CRO**: a compound we’ll purchase as a test of the receipt of open data, as described in this [background post](http://malaria.ourexperiment.org/the_osm_blog/11562) and in #292.\r\n\r\n**The NW Aliphatic**: The des-methyl alcohol is [being prepared by Alice](https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/352#issuecomment-153940665).\r\n\r\n**Sydney Grammar Pyridines**: These are still being purified - [Paul King was looking at them](http://malaria.ourexperiment.org/the_osm_blog/11564). We’re at the stage of attaching the nucleophile in the last step.\r\n\r\n**The Dimethyl Amine**: Needs to be verified based on data from the [last round](http://malaria.ourexperiment.org/biological_data/11080) since methylation of that amine appears to have a profound effect on potency.\r\n\r\n**The Homologous Alcohol**: Good to have, but too lipophilic so needs a re-think.\r\n\r\n**The Homologous Amine**: Ditto\r\n\r\n**The Shackleford**: Blocking group next to alcohol, as per last meeting. This compound fails on cLogP, but may be worth making anyway to test clearance rate. Related issue was to search for commercially-available aryl ethanols #302.\r\n\r\n**The Swain**: Blocking group and benzyl ether. Ditto - may be worth it despite the poor cLogP, or structure could be tweaked? Benzyl ethers still badly explored in this series, so the 2-, 3-, and 4-Cl substituted phenethyl analogs could be checked (suggested by [Chris](https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/301#issuecomment-112443443)) and then [drawn by Alice](https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/301#issuecomment-113038179).\r\n\r\n\r\n## The Desirables\r\n![desirables](https://cloud.githubusercontent.com/assets/4386101/11090021/982137f0-88c2-11e5-96a2-8aeea8e0fcdc.png)\r\n\r\n**Reversed Amides**: These have been discussed, e.g. [here](https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/301#issuecomment-125464563). The synthetic route to this reversed amide series could be through simple amination of the common chlorotriazolopyrazine intermediate, which both Alice (e.g. [here](http://malaria.ourexperiment.org/triazolopyrazine_se/8063)) and Chase are interested in. Chase also suggested azide displacement of Cl followed by reduction to the amine.\r\n\r\n**The AZ Idea**: A group of young scientists at AstraZeneca that includes former OSM-er Matt Tarnowski [recently suggested a cyclic analog](https://plus.google.com/u/0/113168904448483137167/posts/MYCbeZ5NNqV) shown below, and our young contributor Mandrake also suggested some ideas around that molecule. Some cyclic groups [have indeed been investigated in this position](http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series#Pyrazine_Side_Chain_Modifications_-_Others) generally with low potencies - see the summary below. The group joining the side chain to the TP ring (red arrow) can’t be divalent oxygen; we know [simple amine linkers are poor choices](http://malaria.ourexperiment.org/biological_data/10252) (e.g. OSM-S-190), yet amines have typically been the attachment point for rings (see below figure). Carbon linkers have occasionally been OK (e.g. MMV 669304, MMV670243). Perhaps a more polar cyclic group at this position would be OK with a carbon-based linker provided the northwest ring is positioned well. [Metabolic clearance](http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series#Physicochem.2Fmetabolism.2FPK) of carbon-linked compound MMV669304 was atrocious (MMV669304 below), while the related cyclic amine linked MMV668957 was much better (yet much less potent).\r\n\r\n![other linkers on pyrazine](https://cloud.githubusercontent.com/assets/4386101/11090049/cb126cd8-88c2-11e5-9d1e-b3865d9846f2.png)\r\n\r\n## The Hypotheticals\r\n![the hypotheticals](https://cloud.githubusercontent.com/assets/4386101/11090058/d5a696f6-88c2-11e5-8073-955a16fb8a54.png)\r\n\r\n**Crazy Hemiacetal**: Hemiacetals and hemianimals were suggested in the last analog analysis round. They are expected to be too labile, even though [acetals themselves can be OK](http://blogs.sciencemag.org/pipeline/archives/2015/11/05/another-funny-looking-structure-comes-through). While exhibiting a blocking group and good predicted hydrophobicity, this compound is probably too risky. \r\n\r\n**Other Linkers**: [Some of the SAR data suggests the linker between pyridine and Ar ring in the Northwest doesn’t really matter](https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/301#issuecomment-125691401), leading to suggestions of ketone, sulfoxide and sulfone linkers from Chris and a urea [suggested by Chase](https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/352#issuecomment-154147668). We could also investigate a triazole linker (using an alkyne on the pyrazine to avoid a nitrogen-based linker atom on the ring) and an alpha-trifluoromethyl amine as an amide isostere, originally suggested by Chris Burns.\r\n\r\n**The Tianyi**: Rationale for this molecule is that the imidazopyrazine MMV669846 retained potency (vs parent MMV639565) with only a slight deterioration in clearance time (see below), suggesting it might be worth re-examining this compound, but with a blocking group on the imidazole (methyl shown). Named after the student who [started looking at this compound](http://malaria.ourexperiment.org/triazolopyrazine_se/9692), Tianyi Zheng.\r\n\r\n![core mods triazole](https://cloud.githubusercontent.com/assets/4386101/11090073/f2b3cb74-88c2-11e5-9259-06878f04a143.png)\r\n\r\n\r\n**Chase Scaffold Hops**: suggested [here](https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/352#issuecomment-154147668). These will require development of new methods if they’re deemed to be good swaps. Any opinions?\r\n\r\n\r\n\r\n### Misc Other Points\r\n\r\n1) Now that we have more data in the [Master Sheet](http://tinyurl.com/OSM-Compounds), I wonder if we might be able to ask you, @wvanhoorn , to re-do your analysis, prioritizing compounds with untried motifs, using data from Series 4, and with an ALogP cutoff of 3. There was also [mention of results from a matched pair analysis](https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/301#issuecomment-113653493) by Jeremy Besnard - I think the structures are [here](https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/301#issuecomment-116354712). It’d be interesting to see what you get now.\r\n\r\n2) We will shortly be engaging with the OIDD automated synthesis group, and that some of the above synthesis could be part of that collaboration if, for example, a range of reaction conditions need to be screened or a number of analogs need to be generated. #341\r\n\r\n### How to Comment on These Suggestions\r\n\r\nPlease do comment/suggest/criticise. Please do make any of these compounds, provided you share the data so we don't duplicate.\r\n\r\nCommenting can be done below, or on [Twitter](https://twitter.com/O_S_M) or [G+](https://plus.google.com/u/0/communities/105318249049322037798) if you have accounts there. If you have to use email (please don’t) then you can [do that](opensourcemalaria@gmail.com).\r\n\r\nSuggesting structures: you can paste SMILES, or you can easily drag and drop pictures into comments on Github now.\r\n\r\n\r\n### Deadline\r\nNext shipment of compounds to Syngene: **December 15th**.\r\n\r\n(cheminformatic strings for all molecules mentioned in this post are over on the OSM ELN [here](http://malaria.ourexperiment.org/the_osm_blog/8172))"},"comment":{"url":"https://api.github.com/repos/OpenSourceMalaria/OSM_To_Do_List/issues/comments/158990930","html_url":"https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/358#issuecomment-158990930","issue_url":"https://api.github.com/repos/OpenSourceMalaria/OSM_To_Do_List/issues/358","id":158990930,"user":{"login":"wvanhoorn","id":12934826,"avatar_url":"https://avatars.githubusercontent.com/u/12934826?v=3","gravatar_id":"","url":"https://api.github.com/users/wvanhoorn","html_url":"https://github.com/wvanhoorn","followers_url":"https://api.github.com/users/wvanhoorn/followers","following_url":"https://api.github.com/users/wvanhoorn/following{/other_user}","gists_url":"https://api.github.com/users/wvanhoorn/gists{/gist_id}","starred_url":"https://api.github.com/users/wvanhoorn/starred{/owner}{/repo}","subscriptions_url":"https://api.github.com/users/wvanhoorn/subscriptions","organizations_url":"https://api.github.com/users/wvanhoorn/orgs","repos_url":"https://api.github.com/users/wvanhoorn/repos","events_url":"https://api.github.com/users/wvanhoorn/events{/privacy}","received_events_url":"https://api.github.com/users/wvanhoorn/received_events","type":"User","site_admin":false},"created_at":"2015-11-23T16:41:46Z","updated_at":"2015-11-23T16:41:46Z","body":"As was done last summer, here is an analysis of compounds that could be made using interpolation, i.e. using core and Rgroups that have been used before. First the model was rebuilt using the latest 'PfaI EC50 uMol (Mean)'  data from the master spreadsheet:\r\n\r\n![model_enrichment_roc_nov2015](https://cloud.githubusercontent.com/assets/12934826/11341072/bbe998fa-91f8-11e5-87b0-610e1520e2c8.png)\r\n\r\nThe quality of the model is sufficient to use it to select compounds. There are 104 NorthWest substituents which combined with 24 NorthEast gives 2496 possible combinations (per core, only triazolopyrazine core was used). This virtual library was filtered by AlogP <= 3.5 and no amide linkers. Two selections were made:\r\n* Exploitation: top 10 by model score\r\n* Exploration: top 10 by coverage score from compounds with model score > 10. \r\n\r\nThe selections are plotted below: Exploitation = diamond, Exploration = star, Known (already made) = square, Other suggestions from blog = triangle, Not eligible (not passing filter) = grey. The colour gradient is based on model score (blue to red = low to high).\r\n\r\n![alogp_modelscore_nov2015](https://cloud.githubusercontent.com/assets/12934826/11340883/ef2212c0-91f7-11e5-9bc7-9bf5b7737a1e.png)\r\n\r\nThe same compounds (minus the suggestions from the blog) are plotted in the heatmaps below. Exploitation = 1, Exploration = 2, Known = x. The top heatmap shows the effect of the AlogP/amide filter. \r\n\r\n![heatmap_eligible_nov2015](https://cloud.githubusercontent.com/assets/12934826/11340888/f89bdec6-91f7-11e5-8216-82f06fff6dee.png)\r\n\r\n![heatmap_all_nov2015](https://cloud.githubusercontent.com/assets/12934826/11340944/36204ebc-91f8-11e5-9651-b61916598605.png)\r\n\r\nStructures of the selections:\r\n\r\n![selections_interpolated_nov2015](https://cloud.githubusercontent.com/assets/12934826/11341771/dbfce0ae-91fb-11e5-84f5-4e6c1144a8cd.png)\r\n\r\nGsheets with details (including Smiles, InChi and InChiKey. I don't have a tool to calculate IUPAC names in bulk:\r\n\r\nhttps://docs.google.com/spreadsheets/d/1Q14mdFfLInbpqbhLcCpC-1C1pDczIc6oVLJpRZIqUQM/edit?usp=sharing\r\n\r\nAlso as before some transformations have been applied to see if novel structures could be generated. All transformations are based on ChEMBL, i.e. for each transformation there is at least one pair of molecules in ChEMBL that exemplify the transformation. Only transformations that introduce a change in number of atoms <= 4 were attempted. Publicly available filter like PAINS were applied to remove unlikely products as well as QED > 0.5. As with the interpolated designs:  AlogP <= 3.5 and no amide linkers. Similar Exploitation and Exploration picks were made. In the graphs below: colour gradient by model score, Diamond = exploitation, Star = exploration:\r\n\r\n![after_transformations_nov2015](https://cloud.githubusercontent.com/assets/12934826/11342703/962aa8f4-9200-11e5-89a9-42d461305c56.png)\r\n\r\nGsheet of the above selections: \r\nhttps://docs.google.com/spreadsheets/d/1K-FjQIpTWNTEVwyS_4K_RrS_PEGh1EV5iq_sB-271To/edit?usp=sharing\r\n\r\n\r\n"}}