Open Yuhang-CADD opened 2 months ago
to rule out the potential steric clashes of the southwest side of the AZ structure with MurC in the central domain, might help explain the potency drop of the series of AZ5595 amine and guanidinium derivatives, see data in the slides below:
Northeastern contribution, presented by Cole Iannuzzi. Mur Ligase.pptx
Notes from today:
1) @AJLloyd105 presented data from the deck above. The data clearly shows that the AZ compounds are effective against MurC but are not multi-targeting. If the guanadinium compound WYH-76-1-P can be included in any MIC assessments, that would be very good. @Yuhang-CADD to incorporate these data into the table in the draft paper and clarify what data remain to be obtained.
2) Scott Lovell (University of Kansas) is working on soaks: Pae MurC in complex with compound F09 - 3A but not great and no density for the compound. Ditto with Pae MurD with compound M02. Compound A19 binds, but to the surface (is that still potentially useful?). Scott was asking whether we want to soak any other more tightly-bound compounds. The answer is yes, if there is an AZ compound for which we have no structure, but the priority remains getting a structure for a compound from a non-AZ series, towards something that is multi-targeting. @LauraDS1 and @AJLloyd105 recommended trying full length protein rather than truncated, even though harder.
3) @mattodd is pursuing accumulation assay and kinetic solubility assays. Solubility assays are widely available though quite expensive, and we are seeking an alternative solution. Accumulation: @mattodd in touch with Hergenrother's lab and will report back.
4) @LauraDS1 is trying cryo-EM later in July and will report back. Apo first, then with any known binders.
5) The NEU team (Cole Iannuzzi) reported on latest synthesis and next shipment - deck posted above.
6) Next meeting - to be detemined whether it should go ahead, given summer.
Hi, I've updated the presentation I showed (Warwick open source contribution 090724.pptx) by including the replots of data required to extract the Ki values that were included in this presentation. This version is Warwick open source contribution 090724-3.pptx Adrian (@AJLloyd105) Warwick open source contribution 090724-3.pptx
Have obtained the following structures over the past two weeks through HPLC purifications. Awaiting NMR and HRMS to further confirm some of the structures.
Hi, Great! When are you looking to ship? Best Wishes, Adrian
From: Yuhang Wang @.> Sent: Monday, August 5, 2024 3:25 PM To: opensourceantibiotics/murligase @.> Cc: Lloyd, Adrian @.>; Mention @.> Subject: Re: [opensourceantibiotics/murligase] Mur Ligase Meeting July 2024 (Issue #112)
Further Progress Screenshot.2024-08-05.at.15.24.45.png (view on web)https://github.com/user-attachments/assets/51b53f1e-b485-42b2-bda1-ef1d28acb995
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Brief Summary of Aug Meeting:
Warwick contribution to the August 2024 meeting. Analysis of NEU compounds as P. aeruginosa MurD inhibitors 190724-2.pptx
Date: July 9th 2024 & Aug 13th 2024 Time: 2pm UK time other timezones
Place: https://ucl.zoom.us/j/91379419977
Recording:
Jul: https://www.youtube.com/watch?v=084oK1PiXHA&list=PL0eLxnHhou_k1Upbn5X1mdHBwKMYkRpLH Aug: https://ucl.zoom.us/rec/share/WssF3nz4UgQ_E2Uak0tPJGvvQlfidQB7GyLDOeBZQrdJKr885mDLQENS-bo3Skf4.GZKadnkHNGjm6NyC code: S74=UuP9
Previous Meeting: #111 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. Updates on any new IC50 or crystallographic or microbiology data.
ii) New data from Warwick on the contributed AZ compounds (retest at a lower concentration).
iii) Update on crystallographic data of AZ compound 4 (WYH9 compound) in Pae MurD ligase.
(please add if you'd like to prioritise anything)
1) Multi-targeting Compounds from the Warwick/NEU Enamine Collection and Atomwise Compounds
2) Multi-targeting Elaborated Fragments from Diamond Fragment Screen
3) Variants of AZ Compounds
These will include guanidinium and pyridinium derivatives to try to combat efflux.
4) New Protein Structures
No new structures to add to the PDB list.
5) De Novo Computational Modelling
@Yuhang-CADD has paused synthesis of @jhjensen2's originally-suggested compounds (last update was here while the AZ derivatives are being made.
6) CC4CARB Proposal (#93)
7) 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.
8) Mothballs (if no actions then these need to be linked in wiki and closed)
@mattodd is in the process of converting old items to the wiki
Next Meeting
Aug 13th 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.