Murligase Meeting November 2024 #117
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Hi
I might have to offer my apologies for tomorrow- we are in the midst of moving house
Best wishes
Adrian
Sent from my iPhone
On 11 Nov 2024, at 14:06, Yuhang Wang ***@***.***> wrote:
Date: Nov 12th 2024
Time: 2pm UK time other timezones<https://www.timeanddate.com/worldclock/meetingdetails.html?year=2024&month=11&day=12&hour=14&min=0&sec=0&p1=43&p2=136&p3=37&p4=771&p5=235&p6=152&p7=770&p8=250&p9=196&p10=240>
Place: https://ucl.zoom.us/j/91379419977
Recording:
Previous Meeting: #116<#116>
Who can come?: Anyone. No need to say anything unless you'd like to.
Apologies:
Decks: Please @opensourceantibiotics/murligase<https://github.com/orgs/opensourceantibiotics/teams/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<https://github.com/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<https://github.com/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<https://github.com/AJLloyd105> to update on further enzymatic screening of compounds from the Warwick Enamine Collection and Atomwise libraries, following discovery of the hits shown here<#86 (comment)>.
* @LauraDS1<https://github.com/LauraDS1> to update on any soaking and/or co-crystallisation experiments with these compounds, following (last update here<#87 (comment)>.
Update on crystallography trials at The University of Kansas (Scott Lovell, via @bartrum<https://github.com/bartrum>): Compound J06 (Z2010503124).
* @gfsfernandes<https://github.com/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<https://github.com/AJLloyd105> had tested the first batch of compounds from @gfsfernandes<https://github.com/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 ***@***.***<https://github.com/loriferrins> shared https://www.ncbi.nlm.nih.gov/books/NBK442297/).
* In the last meeting @loriferrins<https://github.com/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<https://github.com/LauraDS1> to update on screening (inhibition, SPR, soak) of elaborated Diamond fragments sent by @edwintse<https://github.com/edwintse> in #84<#84>.
3) Variants of AZ Compounds
These will include guanidinium and pyridinium derivatives to try to combat efflux.
* @Yuhang-CADD<https://github.com/Yuhang-CADD>'s 1st batch of fresh samples of AZ5595 and derivatives (Alcohols & Amines) need complete data from @AJLloyd105<https://github.com/AJLloyd105>
* @Yuhang-CADD<https://github.com/Yuhang-CADD>'s 2nd batch of fresh samples of AZ5595 and derivatives (Amines & Guanidiniums) need complete data from @AJLloyd105<https://github.com/AJLloyd105>
* @Yuhang-CADD<https://github.com/Yuhang-CADD>'s 3rd batch of fresh samples of AZ5595 and derivatives (Rigid Small Amines & Guanidiniums & Pyridiniums) need complete data.
* @Yuhang-CADD<https://github.com/Yuhang-CADD>'s 4th batch of fresh samples of AZ5595 and derivatives (Rigid Small Amines & Guanidiniums & Pyridiniums) in progress.
* Accumulation assay - @mattodd<https://github.com/mattodd> to reach out possible collaborators @mattodd<https://github.com/mattodd> will follow up.
4) New Protein Structures
No new structures to add to the PDB list<https://github.com/opensourceantibiotics/murligase/wiki/PDB-and-Fragalysis>.
5) De Novo Computational Modelling
* @mattodd<https://github.com/mattodd> to organise what is known of the competition compounds and what is needed to write the work up for publication.
@Yuhang-CADD<https://github.com/Yuhang-CADD> has paused synthesis of @jhjensen2<https://github.com/jhjensen2>'s originally-suggested compounds (last update was here<#75 (comment)> while the AZ derivatives are being made.
6) CC4CARB Proposal (#93<#93>)
* Successful! Meeting up with committee Aug 6th to plan next steps.
7) Misc/AOB
Last time @AJLloyd105<https://github.com/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<https://github.com/AJLloyd105> to update as appropriate.
8) Mothballs (if no actions then these need to be linked in wiki and closed)
@mattodd<https://github.com/mattodd> is in the process of converting old items to the wiki
Next Meeting
Dec 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.
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Under AOB: @mattodd to ask @LauraDS1 whether they could test some compounds from Institut Pasteur Korea. Also, here are some solubility data for @gfsfernandes compounds, measured by the Uni Barcelona as a contribution to the project. Thanks for them for these measurements, showing good solubility profiles for most of the compounds. @gfsfernandes @alvaro-magalhaes was going to ask whether we could send a couple of these to the other vendor we work with on solubility, Analiza. There are 2 slots free in the next shipment. |
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I spoke with Alvaro, and I’ll prepare two compounds for the plate. |
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I will also show the latest results on Mycobacterium MICs. We tested 25 compounds from this project. |
Complete list
Green: synthesised Complete list of BioData for AZ compounds https://github.com/opensourceantibiotics/murligase/wiki/Microbiology-evaluation-of-WYH-compounds |
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Date: Nov 12th 2024
Time: 2pm UK time other timezones
Place: https://ucl.zoom.us/j/91379419977
Recording: https://youtu.be/IWUdZXlZg9Q?si=ZTYGp7Btl_CHDLM-
Previous Meeting: #116
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 Mycobacterium? @LauraDS1
iii) Update on crystallographic data of AZ compound 4 (WYH9 compound) in Pae MurD ligase (@scott) & AZ5595 (WYH25 compound) in Pae MurC ligase (@LauraDS1 )
(please add if you'd like to prioritise anything)
1) Multi-targeting Compounds from the Warwick/NEU Enamine Collection and Atomwise Compounds
Update on crystallography trials at The University of Kansas (Scott Lovell, via @bartrum): Compound J06 (Z2010503124).
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
Dec 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.
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