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Mur Ligase Firecracker Meeting November 2022 #91
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Progress: Thiazole: the last step to obtain the diol seems to have worked after 3 days of reaction. LCMS indicated the formation of the diol and an epoxide. After purification, I still need to analyze all fractions collected. phenyl imidazole: Suzuki coupling did not work without protecting the Br because a substitution reaction took place. After protecting the Br, I will perform again Suzuki coupling. thiophene: steps 4-7 were done, next steps are in progress. |
Date: Nov 8th 2022
Time: 2pm UK time other timezones
Place: https://ucl.zoom.us/j/91379419977
Recording: https://youtu.be/ZN9VuWB6xFQ
Previous Meeting: #90
Who can come?: Anyone. No need to say anything unless you'd like to.
Apologies: @mattodd
Decks: Please @opensourceantibiotics/murligase remember that if you share slides/info, to drag and drop those into a comment on this page, below. Very easy and saves @mattodd having to pester you.
Agenda:
Key things today are
i) Follow-up screening of multi-targeting compounds from Warwick and Atomwise collections. We need a crystal structure of one or more of these multi-targeting hits to pursue grant funding.
ii) Yuhang's "efflux-proof" amine derivative of the AZ compound was found to bind. Does it inhibit MurC?
iii) Is the rest of the Warwick Enamine collection scheduled for evaluation in the enzymatic assay?
(please add if you'd like to prioritise anything)
1) Multi-targeting Compounds from the Warwick/NEU Enamine Collection
2) Multi-targeting Elaborated Fragments from Diamond Fragment Screen
3) Atomwise Hits
4) Variants of AZ Compounds
5) New Protein Structures
As requested in #90, the the PDB list has been updated with the new, recent structures: 8EGM, 8EGN, 8DOF, 8DP2.
Jan Abendroth has completed the final SSGCID X-ray collection for MurC, in this case with compound AZ-13644923 (AZ compound 26 in the Hameed paper). Deposited with PDB entry 8ewa. Files are here. This completes the series of three AZ compounds bound to this protein. In the two protein chains, the piperidine moiety of the ligand is in two different conformations. Jan's assumption is that the conformation in chain B is the native one, since it does not involve interaction with a symmetry mate. Thank you Jan!
6) De Novo Computational Modelling
@AJLloyd105 reported that the competition compounds had been screened vs. Pae MurD enzymatically. High levels of inhibition were observed, but the compounds all also interfered with the coupling enzymes used in the assay, unfortunately. Solutions: 1) reduce the concentration of the test compounds to find a window where the assay works, or 2) find a different assay. @AJLloyd105 to update. In meeting Should be fine to not worry about off-target effects for now but should be aware that things aren't 100% specific and shouldn't assume they would be.
7) Other Potential Starting Points
8) Misc/AOB
Last time @AJLloyd105 reported on the evaluation, enzymatically, of "double-headed" compounds containing uridine and ATP binders: . These were found to be binders and will be investigated further (need to upload deck). @AJLloyd105 to update as appropriate.
9) List of any Raw Data That Needs Posting Online
Suitable locations: ideally an electronic lab notebook, another suitable repository (Zenodo, Figshare) or Github itself.
9) Mothballs (if no actions then these need to be linked in wiki and closed)
Next Meeting
Dec 13th 2pm UK time - the Christmas Present
L'esprit de l'escalier
If you'd like to follow up after the meeting, please comment below. You can also email, but please be clear if anything in the email should not be public domain - the default is always open.
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