1/ It's been a very busy few weeks in the Walsh group @diamondLightSou but extremely happy to announce that in collaboration with Frank von Delft group’s at Diamond we have been able to perform a full X-ray fragment based drug discovery experiment on the SARS-CoV-2 main protease 
2/ We have released all data from this work here: diamond.ac.uk/covid-19/for-s… #covid19 #SARS_COV_2 #DrugDiscovery #AntiviralDrugs #structuralbiology #crystallography #cryoEM #nmr We will update data as its generated to accelerate drug development to combat #COVID19 @JeremyFarrar
3/ This has been an amazing team effort involving on the science side my group (Petra Lukacik, Claire Strain-Damerell & David Owen) and Frank von Delft's XChem Team (Primarily Alice Douangamath, Daren Fearon) and Ailsa Powell from the @DiamondILO @EJShotton team
4/ I thought it would be useful to share how we got from gene to structure to initiating a structure based drug discovery project so you can get a sense of how the last few weeks have evolved in my group @DiamondLightSou and hopefully share in some of the #excitement
5/ On ~26th January Dave Stuart @DiamondLightSou received a call from Zihe Rao @ShanghaiTechUni Rao’s group with Haitao Yang’s had solved the structure of the main protease with the covalent inhibitor (N3) and were making coordinates available by request
6/ They were slowed down by a shutdown in the Shanghai synchrotron and asked for help, so we mobilised time and resources in Diamond to accommodate automated data collection from their crystals (Led by Dave Hall MX group leader at diamond ) worry was shipment of materials meant..
7/ On the 31st Jan we dropped everything we were doing and ordered synthetic gene...(protocol europepmc.org/article/med/17… very cool paper, do check it out) which arrived on the afternoon of the 10th Feb. All hands on deck to generate pure SARS-COV2 main protease by the 14th February
8/ crystallisation experiments were immediately setup. However we knew from our collaborators (Zihe Rao group Shanghai Tech and Xiangxi Wang CAS Institute of Biophysics Beijing) that obtaining ligand free crystals of the main protease was problematic
9/ They had made an heroic effort and made available the structure of SARS-COV-2 main protease complexed to the inhibitor N3 - which was released by the PDB on 5th Feb as 6lu7 @PDBeurope @buildmodels rcsb.org/news?year=2020…
10/ ..First crystal hits from crystallisation trials were observed 24 hours later on the 15th feb ..@ActaCrystD @NatureSMB @Structure_CP
11/ Don't judge a book by its cover...optimisation by seeding gave us something that looked hopeful on the 18th Feb. These crystals were tested on beamline I04 at @Diamond_MX ..amazingly these diffracted to 1.9 Å resolution
12/ These data allowed us to solve the structure but more importantly showed it had the active site empty and solvent accessible -- perfect for fragment screening. Very happy group! and was then time to call on our XChem colleagues at beamline I04-1 diamond.ac.uk/Instruments/Mx…
13/ By 19th Feb we knew we could grow crystals quickly so this gave us the opportunity to improve diffraction, while also producing crystals for the XChem team to assess how resilient the crystals were to conditions for soaking experiments..better xtals quickly produced
14/ these crystals were assessed under different soaking conditions by the XChem team and data collected to assess what would worked best for soaking with fragments on 24th feb. The crystals diffracted well and more #excitement as data were collected to beyond 1.4 Å resolution!
15/ This provided the XChem team with an excellent reference structure for the first XChem campaign. The structure is deposited with the PDB @PDBeurope ID 6Y84 Mar 11th release date but you can download now from the experiment and results section here: diamond.ac.uk/covid-19/for-s…
16/ high resolution screening of #SARS_COV_2 main protease crystals made possible by Katherine McAuley & Mark Williams on I03; Ralf Flaig & David Aragão on I04, Jose Brandao-Neto on I04-1 & Adam Crawshaw VMXm. @UKRI_News @The_MRC @bbsrc @stfc
17/ Pure samples of SARS-CoV-2 main protease shipped to Nir London’s group @london_lab @WeizmannScience where electrophilic fragment screening by mass spec was carried out on 25th feb. Work enabled by XChem collaboration, crucially supported by @instructhub #H2020
18/ By the 26th February the XChem team had mounted over 600 crystals and the first fragment screen was launched. The results can be downloaded here: diamond.ac.uk/covid-19/for-s… @wellcometrust @STFC_Matters
19/ in parallel we have made a series of suitably tagged constructs of the SARS-CoV-2 main protease and sent these to @exscientialtd on the 3rd March taking advantage of their AI platform for hit to candidate drug discovery. #SARS_COV_2 #drugdiscovery
21/ Credits for all this here:diamond.ac.uk/covid-19/for-s… Important to note the amazing software developed within Frank von Delft's group
22/ We couldn't have done any of this without the state of the art facilities @DiamondLightSou - can't name everyone here but thanks especially to mx beamline techs, engineers, support groups - controls, data acquisition, data analysis and automated software developments..
23/ Have to also thank diamond user office; technical division for extending the shutdown to allow us and other users working on #SARSCoV2 projects to complete experiments. Important thanks to admin, contracts and finance teams for helping us focus on the science...
24/ and final thanks to Diamond communications team for putting together the #COVID-19 webpages and massive effort and support they provide in making the science accessible to everyone -do get in touch with your science enabled @DiamondLightSou and they can also help publicise
25/ Our #covid-19 #sars2cov2 web pages have info for scientists, the public and media here: diamond.ac.uk/covid-19.html results and data made available as rapidly as possible vs the normal peer-review publication route to help inform the public health response and save lives.
