Mur Ligase Online Research Meeting 2pm June 8th 2021

[mattodd]

Meeting follows on from May 2021 meeting at #43. When: Tue June 8th 2pm London (BST). Where: https://ucl.zoom.us/j/99344325484 Recording: https://youtu.be/q64K7qyGNs8

Actions from Last Time

• [ ] @WieselHenson to complete the synthesis of the AZ alcohol compound
• [x] @mattodd and Chris Dowson and Frank von Delft to chivvy MTAs for Atomwise compounds.
• [ ] @Rebecca-Steventon to post data of @LizbeK fragment screen and perform screen of @danaklug elaborated fragments.
• [ ] Laura to continue crystallisation trials of MurD and MurE in Warwick, with the plan to take crystals to Diamond
• [ ] @eyermanncj, Chris and @bartrum to pursue AZ compound shipment for crystallisation trials.
• [x] Chris Dowson and @mattodd to apply for ANTRUK funding (Deadline May 28th), with inputs from others
• [x] @mattodd to coordinate submission to ELF Call https://www.europeanleadfactory.eu/how-submit/supporting-documents-proposal-submission by May 28th again with inputs from others.
• [x] Chris D to reach out to Chris Schofield re previous antibacterial screens at ELF.
• [ ] @jhjensen2 to extract in vitro inhibition data from published literature and use towards the construction of a predictive model.
• [ ] Peter Horanyi to continue crystallisation of e.g. MurC with Enamine compounds sent by @eyermanncj. (Structures here from @loriferrins)
• [ ] Chris Dowson to liaise with others to establish protein needs, and what's needed from SSGCID.
• [ ] @mattodd and Chris D to interact with Alphafold. With Laura they'll come up with a defined piece of work and circulate.
• [ ] @bartrum to liaise with David Baker lab about potential protein structure prediction work.
• [ ] Laura to liaise with Peter and Lizbe to see if a soak of the @eyermanncj Enamine compounds is possible at Diamond.
• [ ] Following some discussion at May meeting, @eyermanncj asked whether there might be the possibility of a biochemical screen against another non-ATP site, and Chris D would chat to Adrian about that.
• [x] May meeting posted to Youtube: https://www.youtube.com/watch?v=YzJ-1-FvwsQ

Overall Aims remain: i) Structures of two mur ligases bound to the same small molecule. ii) Identify new starting points for inhibitors.

Another future aim: devise platform agreements within OSA in order to simplify the MTA-related paperwork, which is proving problematic. Could we transform OSA into a charity (though since none of us would work for this charity, it's not clear how much that might help).

Also: entering the 600 or so Enamine compounds purchased by @eyermanncj into an xchem screen at Diamond. A soak vs Psuedomonas MurC. @LizbeK was going to email details of the compounds. Laura to liaise with Peter and Lizbe to see if this soak of the Enamine compounds is possible.

Next meeting: Tuesday 6th July 2pm London Location:

[phraenquex]

@mattodd we've passed on the MurE data to the group of Alex Tropsha at UNC (well, we pointed them to Fragalysis): they've got an NIH grant to do computational design of molecules, AND money to buy compounds... I'd written a letter of support, and a few months ago they asked for targets. It was a no-brainer to drag them in; I think they're still tooling up a bit, but the moment they ask for more, we can point them to other issues. I don't think we have timelines yet, but we're meeting them every other week (they have other TEP targets too, for practical reasons.)

[Yuhang-CADD]

[Rebecca-Steventon]

Here is the link to the page with the data from Lizbe's fragment screen: https://github.com/opensourceantibiotics/murligase/wiki/Allosteric-Pocket

[mattodd]

That's great, thanks @Rebecca-Steventon. FYI All: additions to the wiki (like this one) don't result in alerts in the same way as if things are added as updates to Issues (like this).

[mattodd]

Hi @phraenquex yes I think I was on that email chain - I'm v happy to jump in to your call if it helps align. I think what they're planning on doing re elaboration of the mur ligase fragments makes a huge amount of sense, particularly if the early promising results from @Rebecca-Steventon on @danaklug samples bears out.

Or Alex (@TropshaGroup) comes to the next mur ligase meeting on July 6th...