Yuhang-CADD
commented
7 months ago 1st round compounds (shipped & tested)
Adrian's update on the following results in Page MurC:
WYH76-1-P (OSA_001174) [Guanidinium derivative of WYH30-X-P (OSA_001111)] Lowest potency among the 1st round compounds. But still worth trying the guanidiniums in vivo to see if eNTRyway rules and additional penetrating features.
AZ compound 11 (WYH17-X_P) Ref IC50 = 0.008 uM Adrian IC50 = 1.12 +/- 0.22 uM
Novel compound, stereoisomer of AZ compound 13 (WYH77-1-P)/(OSA_001175)
AZ compound 13 (WYH78-1-P)/(OSA_001176) Ref IC50 < 0.0005 uM
AZ compound 4 (WYH9-X-P)/(OSA_001044) Ref IC50 = 0.008 uM
AZ5595 (AZ compound 10)/(WYH25-X-P)/(OSA_001071) Ref IC50 = 0.001 uM
Summary for this topic:
The mismatch between the published and the actual inhibition data was potentially due to different methodologies being used. As Adrain has reflected, the precise description of the concentration range (in the Hameed paper) over which their IC50s were determined was no where to be found. Also, the assays employed in that paper are also significantly different in their design, their employed substrate concentrations and readout.
Thus, Adrian is working on re-testing these compounds at a lower concentration range for more accurate data.
Currently, only the potent compounds would be tested as the UDP MurNAc in his lab are running low and needs to re-synthesised. Will be available in early March for more MurC inhibition tests.
2nd & 3rd round compounds (will have a corresponding code after characterisation):
The dark green structures are the ones I am currently working on. The black ones are of lower priority as either reaction conditions haven't been finalised or starting materials haven't been synthesised.
Double check with Joe's suggestions on further designs of AZ series to avoid efflux potential. Reducing HBD is the key.
New Crystal Structure
AZ Compound 4 (OSA_001044, WYH9-X-P) shipped as solids (12 mg) to Scott (Protein Structure and X-Ray Crystallography Laboratory, University of Kansas). This compound was having a good multi-targeting potential and thus will be soaked in Pae MurD for illustration of interactions. This data is crucial for obtaining an idea for furture modifications of this series of compounds.
AJLloyd105
s-spijkers-shaw
Date: Feb 20th 2024 Time: 2pm UK time other timezones
Place: https://ucl.zoom.us/j/91379419977
Recording: https://www.youtube.com/watch?v=4LowyO259jw
Previous Meeting: #106 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.
(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
Mar 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.