Online Mur Ligase Research Catch-up Nov 2020

[mattodd]

This is a placeholder issue for the next catch-up.

Meeting will be held as follows:

Topic: Mur Ligase Research Catch-up Nov 2020
Time: Nov 4, 2020 01:00 PM London

Join Zoom Meeting
https://ucl.zoom.us/j/92928164336?pwd=Zk84bHoxaDBEN1RNcHlmUzhVVnZJdz09

Meeting ID: 929 2816 4336
Passcode: (ask any attendee, e.g. me, @danaklug @drc007 )

Meeting took place, here are minutes:

1. 96 Atomwise compounds have been received in UCL (Atomwise molecules #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.

2. 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.

3. 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.

4. 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.

5. 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).

6. 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.

[danaklug]

Closing, these notes have been captured in the wiki