yiwei905
commented
1 year ago MurE inhibition data for multitargeting hits sent on the 23rd May and 25th July 2023, including synthesised derivatives of compounds AW53 by @yiwei905, AW9 by @EveCarter, as well as derivatives of the multitargeting compounds bought from Enamine, and 2 competition compounds by @edwintse as summarised here.
MurD inhibition data +structures were also attached: P. aeruginosa MurD inhibition.pdf
P. aeruginosa MurE Inhibition Data of Multitargeting Hits.pdf P. aeruginosa MurE Inhibition Data of Multitargeting Hits.docx
bartrum
Yuhang-CADD
AJLloyd105
mattodd
phraenquex
chrisdowson1
Date: Sep 12th 2023 Time: 2pm UK time other timezones
Place: https://ucl.zoom.us/j/91379419977
Recording: https://youtu.be/XrB8R_32bB0?si=ySufgClfVFvOCbkZ
Previous Meeting: #101 Who can come?: Anyone. No need to say anything unless you'd like to.
Apologies:
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) Multi-targeting compounds identified 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 by SPR, but gave no activity vs wt bacteria (data on wiki and a summary of data in #96. Need to complete checks of enzymatic activity of these compounds, to verify the design is OK in terms of enzyme inhibition. (Still awaiting for the IC50 values)
iii) When would the rest of the Warwick Enamine collection be scheduled for evaluation in the enzymatic assay?
iv) Shall we suggest a booking & tracking system where people can book period slots for fresh sample testing (easy to arrange shipment and avoid sample deterioration) and see the results remotely in real time? (e.g., we could set it up on google sheet as a live document.)
(please add if you'd like to prioritise anything)
1) Multi-targeting Compounds from the Warwick/NEU Enamine Collection
Crystallography at The University of Kansas: J06 (Z2010503124) had also been sent to Uni Kansas (Scott Lovell, via Bart).
2) Multi-targeting Elaborated Fragments from Diamond Fragment Screen
3) Atomwise Hits
4) Variants of AZ Compounds
5) New Protein Structures
The PDB list has been updated with the new, recent structures: 8EGM, 8EGN, 8DOF, 8DP2, 8EWA. Jan Abendroth has completed the final SSGCID X-ray collection for MurC, with 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
7) Other Potential Starting Points
8) CC4CARB Proposal (#93)
Following discussions between @eyermanncj @Yuhang-CADD and @mattodd a proposal is being written for CC4CARBfunding to help with chemistry aimed at exploring more potential binding interactions with the Murs, specifically areas where phosphates normally bind.
9) 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.
10) List of any Raw Data That Needs Posting Online
Suitable locations: ideally an electronic lab notebook, another suitable repository (Zenodo, Figshare) or Github itself.
11) Mothballs (if no actions then these need to be linked in wiki and closed)
Next Meeting
Oct 10th 2pm UK time
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.