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Nov. 4, 2020
Meeting minutes:
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96 Atomwise compounds have been received in UCL (#33). Need to ship these to Diamond and Warwick. Awaiting tweaking of contract between UCL and Atomwise to allow for this. ACTION Frank and Chris D to forward emails of appropriate people who can deal with this.
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Results from MurE screens at Diamond. No hits (i.e. structures with compounds bound) from elaborated fragments, and the original hits were re-tested and did not co-crystallise either. What to make next?
Need to identify one site with multiple binders and do a design/merge. Need volunteers to perform the merge.
If there are not enough overlapping binders, maybe perform another screen? Perhaps with substrate bound, to help? Frank said there was a cluster of 10 in fragalysis. Action on @danaklug to post summary of the clustering (and where bound). Yuhang said there are few structures known with ATP bound - @eyermanncj said that's not correct, and (Action) would connect with Yuhang to clarify.
- MurD evaluation of UCL elaborated fragments/Enamine (600 compounds) in Warwick. This is needed when protein is available.
Adrian said strep enzyme was being used. A swap of Mg for Mn was made in the assays. Shifts Km in the right direction to allow for assessment of weak binders. Sounds great.
Action Mat to reconnect Chris D and Bart to discuss protein supply.
- Modification of known leads, e.g. AZ compound/MurC.
At UCL, @WieselHenson and @dayang-us are looking into in silico modification of AZ compound bound to MurC. e.g. replacement of OH with NH2 to improve eNTRy criteria.
Action: Chris and Adrian to dig out old MurC project. Currently in -80 freezer. Would be very good to do crystallisation of these ADP site binders.
Action: @eyermanncj to investigate possible AZ contacts to discuss compounds made/evaluated but not published.
- Presentation we're making to NIAID as part of Bart's meeting with them.
Action on Mat to assemble deck, with advice from all.
Slides on: science (dual inhibition to overcome resistance), track record of whole team (that has worked together, and shares a belief in this approach), that it is open (to improve the science) and that we have a clear translational plan (M4ID).
- AOB
a) @eyermanncj mentioned a literature effort (Notre Dame project?) that found a compound that inhibited more than one mur ligase. What was the structure? Action on Joe to post, alongside potency.
b) Chris D suggested a GANTT chart to highlight what resources we have for this project, and for how much longer. Action on Chris to start this.
c) Action on all: Please sign up for Github if you've not already and send @mattodd your user ID.
d) Next meeting will be Wednesday December 2nd (update: Dec 8th) at 2pm GMT. Action on Mat to forward a calendar invite. We will include a more formal agenda, with ppt updates from the respective teams to help ensure everyone is up to speed and there is a record of progress.
Relevant GH Issue: #26