20180813 jose, ray, floriano, lauro, rafael, nick f

20180612 - fragalysis session - anthony b, jose b, nick f

• Where are the PDBs that nick had refined in the lb16978-1 folder
• zpv37239 - nick's fedid
• nick can't see the models in xce-coot-in-refinement, and only can see event maps but no models. 
• /dls/labxchem/data/2017/lb16978-1/processing/analysis/initial_model/PROTEIN-x2258

20180809 - Floriano, Lauro, Nick, Jose', Ray, Fabiano

• Jose' to provide Floriano with info about missing compounds
• some other actions
• Lauro arrives on 13-08
• Floriano will be in UK 29-08 to 07-09

20180504 contact by angelucci

• Angelucci contacted back about network collaboration

20180502 Newton prize

• Floriano sent materials about application at the end of May 2018

20180424 ray, jose, nick, floriano

• ACTIONS IN YELLOW 

 

• hit follow up: Nick to talk to Anthony B to organise the follow up with the 60% hits that were validated with XCE
• jose spoke to F angelucci and colleague on 15-04-18:
• Dear Francesco,
  Thanks for that. From the discussion between you, I and your colleague Rodolfo we agree that a network expansion could take place and that a few people will have some overlapping interests and a good way forward is to establish collaborations with clear terms. I suggest a memorandum of understanding style where the uk-br network says what they intend to do and how both parties see how they can benefit and possibly making clear some exclusions upfront?
  We (Diamond, OPPF, LSTH, Fiocruz) have to participate is this: We are interested in SmTGR as a system that can have new drug leads discovered using fragment based lead discovery but also in creating the pipeline and network of groups that can be used for lead discovery for other targets as well. My direct collaborators are Raymond Owens from the OPPF-UK, Nick Furnham from the LSTH (UK) and Floriano Silva (Fiocruz-Brasil) and we have an SmTGR construct (no Se-cys) which we used to do an xchem fragment screen (600 fragments) and are now preparing the first fragment hit series follow-up, growing from the fragments with the support from the OxXChem facility (Anthony Bradley and F von Delft-UK). We also have phenotypic assay and chemistry collaborators for later series developments (Brasil). Apart from TGR, the UK-BR team is interested in creating a platform/network to enable other (neglected disease) targets to go through the same process through the network. We currently have a small grant to fund ~150 follow up fragments to: do crystallography with the hit follow ups and assess binding in vitro. This is to happen between June and December (1 person, 3 months effort).
  An example collaboration with the IT-US network and develop an active follow-up informed by the fragment screening.
  Another example of mutual benefit would be to perform fragment screening on the Sec construct. You asked about the electrophiles. We have a library of covalent compounds from a London group that could be used, for instance. What do you have in mind regarding the electrophiles?
   
• ian gilbert from dundee spoke to nick about collaborating re schisto in Schisto in a parasitology meeting in Aberystwith.  belgium group on epigenetics targets.
•  ray brought up that lab 282 evotec collaboration sounds similar.
• floriano mentions MMV pathogen box screening  in vivo hit which has one of high content TGR hits as substructures 
• one is 10uM concentration probably another target as well
• ic50 ~ 100uM
• active against TB
• nick mentioned innovate uk grant
• fiocruz has and targets juveniles (unaffected by PZ
• Q)
• metabolic label XTT adapted from schistosomula
• karl h has schistosomula and developing assays for adults
• california has high content assay
• floriano on to newton prize 2018 exclusive for £200k
• include xchem in proposal
• floriano to ask for support letters from participating researchers
• letter by 10-05. deadline 25-05-18
• Lauro: 2nd-3rd week July: for 2 months 
• Ray organising SPR at RCaH, initially with NADPH
• FAye's and Nick's list and prioritise 50 off
• jose mentioned the x-ray experiment is likely causing an x-ray-induced artifact which buries the compound signals.
• pasteur uruguay can produce Sec-SmTGR in e.coli.
  

20180418 Location of TGR protein in RCaH

• PPUK freezers
• Freezer -80degC number 8
• bottom door
• right hand most stack
• top drawer: there are preps from barbora and valteri, plus preps from the other constructs (with alanine and with Sec).
• Ray to send jose the sequences for each construct.

20180209, 20180213, 20180219, 20180220 pandda rerun prep

• @nick: what set was in spacegroup A and what in sg B? and the datasets you found hits? 
• @jose: split in know sets and rerun pandda there.
1. changed the database and analysis folders: moved nick's original processing to a subfolder inside analysis; renamed the original .pkl file.
2. visit /dls/labxchem/data/2017/lb16978-1/processing/
1. only lb16978-2 selected in the beamline folder
2. 475 crystal folders in analysis/initial_model lifted with xce 
3. compound files: 
1. 455 x 3 compound .cif, .pdb and .png files found
4. using the datasets autoselected as C2: 
1. 108 datasets selected for dimple
1. 107 dimple.pdbs returned
2. x2095 is the starting C2 model 
3. jose left refine-c2-ground-jose.pdb in the reference folder (this is pretty much like smTGR-c2.pdb apart from the waters).
2.  started a pandda "pre-run for ground state" with those 107 datasets
5.  and now, the ones autoselected a/dls/labxchem/data/2017/lb16978-1/processing/references P2 or P21
1. 171 marked for dimple with the P21_orig model
1.  x2064 is the starting from p21_orig
2.  dimple reran with p21_alt model
1.  x2047 is the starting model for p21-alt
6. I moved the ground state effort files so they don't clutter the folders. /dls/labxchem/data/2017/lb16978-1/processing/reference moved to /dls/labxchem/data/2017/lb16978-1/processing/reference/ground-state-model-effort
7. CONCLUSION:
1. from the assessment of the average maps created in the ground state model process, I don't think it's worth modelling a ground state different than what nick had already modelled originally. Yes, it would tweak the waters, but it's just more effort than necessary. Keep the 3 original models to redo pandda: SmTGR-c2.pdb, smTGR-p21-alt.pdb and smTGR-p21-original.pdb. They're the only ones in the reference folder now.
• @all: 16-02 to review pandda rerun with current softwareand others.