Murligase Meeting October 2024

[Yuhang-CADD]

Date: Oct 8th 2024
Time: 2pm UK time other timezones

Place: https://ucl.zoom.us/j/91379419977

Recording: https://youtu.be/anFhXvaSsn0?si=qNI_yGs27cjgUTcZ

Previous Meeting: #115
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 (including MICs, retests of IC50s at a lower concentration). Also, any updates on AZ compounds vs TB? @LauraDS1

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

• @AJLloyd105 to update on further enzymatic screening of compounds from the Warwick Enamine Collection and Atomwise libraries, following discovery of the hits shown here.
• @LauraDS1 to update on any soaking and/or co-crystallisation experiments with these compounds, following (last update here.
  Update on crystallography trials at The University of Kansas (Scott Lovell, via @bartrum): Compound J06 (Z2010503124).
• @gfsfernandes to update on current research in design of improved binders vs TB murs. Note - new repository for this project at https://github.com/opensourceantibiotics/Series3-TB_MurLigase. In last meeting, @AJLloyd105 had tested the first batch of compounds from @gfsfernandes vs MurE. There was some inhibition of the coupled biochemical assay. High concentrations were needed, which raises queries about solubility (which should be measured for these compounds). Another assay was employed, with methylthioguanosine. We probably need SPR, or something else biophysical, though ADP-glo is also possible. Several compounds gave some evidence of inhibition (e.g. GF-62) and IC50s will be measured. It is possible that aggregation may also be affecting these compounds (@loriferrins shared https://www.ncbi.nlm.nih.gov/books/NBK442297/).
• In the last meeting @loriferrins and team (Sam Spijkers-Shaw, Thomas ("Tommy") Waltz-Chesnaye and Cole Iannuzzi (taking over from Tommy) reported. Compounds to be shipped to Warwick then AZ.

2) Multi-targeting Elaborated Fragments from Diamond Fragment Screen

• @LauraDS1 to update on screening (inhibition, SPR, soak) of elaborated Diamond fragments sent by @edwintse in Compound to Warwick Inhibition Assay Jun 2022 #84.

3) Variants of AZ Compounds

These will include guanidinium and pyridinium derivatives to try to combat efflux.

• @Yuhang-CADD's 1st batch of fresh samples of AZ5595 and derivatives (Alcohols & Amines) need complete data from @AJLloyd105
• @Yuhang-CADD's 2nd batch of fresh samples of AZ5595 and derivatives (Amines & Guanidiniums) need complete data from @AJLloyd105
• @Yuhang-CADD's 3rd batch of fresh samples of AZ5595 and derivatives (Rigid Small Amines & Guanidiniums & Pyridiniums) need complete data.
• @Yuhang-CADD's 4th batch of fresh samples of AZ5595 and derivatives (Rigid Small Amines & Guanidiniums & Pyridiniums) in progress.
• Accumulation assay - @mattodd to reach out possible collaborators @mattodd will follow up.

4) New Protein Structures

No new structures to add to the PDB list.

5) De Novo Computational Modelling

• @mattodd to organise what is known of the competition compounds and what is needed to write the work up for publication.

@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)

• Successful! Meeting up with committee Aug 6th to plan next steps.

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

Nov 12th 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.

[Yuhang-CADD]

Adrian's latest data (NEU contributions):
Aug 2024 NEU cpds.pdf

[Yuhang-CADD]

4th Round Shipment Ready:

Laura Atomise Resistance Sample:

Laura Xstallography Sample (with Full-length Pae MurC)

AZ Noval Derivatives

AZ Guanidinium Development

Need to try other conditions? Necessary? What would reviewers say?

AZ Pyridinium Development

[Yuhang-CADD]

Adrian's contribution:
OSA Contribution 081024.pdf

[Yuhang-CADD]

Adrian's contribution:
Yuhang 4th round MuurC inhibitors 081024.1.pptx