Open danaklug opened 3 years ago
miike
commented
3 years ago Separately, @mattodd found that the OSA molecule spreadsheet is not indexed.
This might be because the document has been published to web (e.g., you can visit it via the URL but it won't be crawled automatically).
drc007
commented
3 years ago @miike The spreadsheet has been published to the web, and you can search and find the spreadsheet. However, the contents of the spreadsheet seem not to be indexed.
miike
commented
3 years ago @drc007 I've had a look at the permissions - I think the permissions need to be set to:
which seems to be the same permissions in some other sheets that are indexed correctly by Googlebot.
mattodd
commented
3 years ago Hi all - good meeting today, thanks for the inputs.
Molecules suggested for Paul Stapleton's MSSA assay, to check for efflux as a reason for the potency ceiling:
821 our general +ve control
820 our general -ve control
842 contains benzyl amine
865 contains p-methyl and is nicely potent
851 contains aniline
The dimethyl amine amide 974 - see #46. I'm not sure that's worth it.
How about one of the pyridine isomers e.g. 873 or 874 to check that this motif is not inactive because of efflux?
All these are slightly disappointing, and so are good to check.
On @danaklug: How do these molecules look with respect to the Hergenrother Entry criteria? (Online tool is http://www.entry-way.org )
(Action also on @danaklug to add potency data in #46 to the wiki tables).
Discussion of tox was interesting. There is indeed some sensitivity in the data and it'll be important to reassess trends when we have the new data from Andreas etc. At that point let's decide whether to trigger Lee's repeat experiment.
Thanks to @drc007 for agreeing to ask around about evaluation vs existing bacterial lines that are drug resistant, as a probe for MoA.
@miike - thanks for the advice above. We're not sure what the issue is. Can you see the sheet and check the permissions? We're a little stumped.
MFernflower
commented
3 years ago @mattodd I ran some molecules through the entryway algorithm - results are below:
974 - fails primary amine check NEGATIVE control - fails primary amine check POSITIVE control - fails primary amine check Para-Cyano - fails primary amine check Pyridine to Pyrimidine swap (874) - fails primary amine check
All these compounds pass 2 of 3 tests in the algorithm regardless if active or not
miike
commented
3 years ago @miike - thanks for the advice above. We're not sure what the issue is. Can you see the sheet and check the permissions? We're a little stumped.
I don't think I have permissions to modify / update this sheet at this stage.
If we get really stuck we can mirror the sheet (a non-editable form) and host on Github (which will get indexed) as a last resort.
drc007
commented
3 years ago @miike Try this link https://docs.google.com/spreadsheets/d/168-a1_l51Nfbms67eG8zU8p-EhEtEO26FUzRInbu7fY/edit?usp=sharing I think anyone should be able to edit?
mattodd
commented
3 years ago @MFernflower - thanks. Yes, I know the primary amine check was not promising...but all the other two (globularity and something else) passed? That's interesting.
MFernflower
commented
3 years ago @mattodd @danaklug @drc007 The other two checks seem to be mostly for how bendy a molecule is - since our compounds are super rigid - all of them pass even if they don't kill MRSA (see image of me testing this software with some perfume chemicals below)
danaklug
commented
3 years ago See below for the Entryway results on the compounds mentioned by @mattodd above (CSV file found here).
I added the color-coding based on cutoffs mentioned in the Hergenrother paper: "In general, primary amines with five or fewer rotatable bonds and a globularity of 0.25 or less have a markedly higher likelihood of accumulation..." All I could find about PBF is that it's another way of looking at three-dimensionality, but for our purposes it doesn't seem to be as important as the other three criteria so I've not closely analyzed those results.
Our compounds are well within the rotatable bond and globularity parameters but we're missing the crucial addition of a primary amine (as mentioned by @MFernflower) and I think we should be thinking about how to incorporate this functional group in future designs. One idea I had was to add this to our library of amines on the northwest substituent:
MFernflower
commented
3 years ago @danaklug Also for consideration this boronic acid is commercially available and 250 mg of it is cheap
miike
commented
3 years ago @miike Try this link https://docs.google.com/spreadsheets/d/168-a1_l51Nfbms67eG8zU8p-EhEtEO26FUzRInbu7fY/edit?usp=sharing I think anyone should be able to edit?
Google seem to have completely disappeared the 'Publish to the web' option from their user interface. I'm going to look into an option to mirror the spreadsheet on an OSM github.io domain as I think we'll have better luck getting it indexed there.
miike
commented
3 years ago @drc007 I've setup a page to mirror the Google sheet here: https://opensourcemalaria.github.io/os-antibiotics-molecules.html with the hope that Google Bot will have more luck crawling this domain. I've also added and verified it with Google Search Console so we should have a clearer idea of when / if it's being indexed correctly by Google.
drc007
commented
3 years ago @miike Fingers crossed!
Meeting Feb 5th 2021 at 2pm UK time at https://ucl.zoom.us/j/92800004715. This page follows on from #53.
Recording is here.
On the call:
a) Potency A summary of new targets discussed for the next round of may be found here.
The earliest Paul Stapleton can accept compounds for MRSA screening is Feb 16. New targets will likely not be ready, but Lori's submitted compounds (#48) can be screened.
Paul can also screen for MSSA in order to probe whether our compounds are being effluxed by MRSA. Action: Decide which compounds to include in this assay.
b) Human Cytotox Underway in the lab of Andreas Schatzlein. This is also to test the metal-binding potential of the 2-pyridyl system. Updates will be at issue #3 .
Recent update from Alex: “The main concern I had was that we were not able to reproduce the CC50 for tamoxifen which is the standard used in the CO-ADD protocol ... We have resolved this issue now and I think we have the optimum procedure such that we can trust the data. I expect we will have data from enough repeats to share with you in a couple of weeks' time - so perhaps at your Friday meeting on the 12th.”
Some discussion of the tox data for NEU compounds has taken place at #3.
Synthetic Chemistry The Google doc shopping list has been updated (see below). @danaklug to place orders by end of Jan. A list of all recently proposed targets may be found here and synthetic routes to most are outlined here.
in vitro PK Hypha results are in at #50 and will be discussed there. No action currently needed. Update Feb 15th. Sample likely ready March 1st.
Community updates a) Newsletters. Action on @mattodd to write the second newsletter. Being formulated at opensourceantibiotics/murligase#37
Molecule contributions Terms discussed in #45, with new revision (discussed more at mattodd/blog#1). Terms have been updated on OSA Series 2 wiki and on the Google form here.
Action: ensure that the idea of molecule donations is placed somewhere prominent and then remove this item from the agenda.
Action on @edwintse to ensure the data are also installed on Labarchives and linked to Github, to ensure we don't lose such crucial files.
Action: Update wiki with experimental details and results.
Action: Compile results of literature searches on targets of interest (mquo1, purD) and whether there are biochemical assays available.
Action: Decide on next steps.
AOB
Actions
[ ] ACTION ITEM: This meeting to be posted on YouTube.
NEXT MEETING IS ON FEBRUARY 19th