jelenaUCL
commented
6 months ago Open TomkUCL opened 7 months ago
jelenaUCL
commented
6 months ago 
TomkUCL
commented
6 months ago 
mattodd
commented
6 months ago I chased Joe Newman about the Nsp13+ATP periodate thing and, to paraphrase, he said: "I have done several soaks in the last few weeks including with ATP periodate. I previously had some data with this compound that looked ok but I wanted to get better resolution to see more details. The latest rounds actually didn’t look any better (the resolution was good but this time noting convincing for the electron density). I have some ideas why (it seems that soaking out the phosphate might be required) and hope to try again in the new year. I will also take a look back on the older data to see if I can get a more confident model." With thanks to Joe for this update, and we'll include it on the agenda of the next meeting.
TomkUCL
commented
6 months ago Here is my complete analysis of the Core1 Enamine carboxylic acids enumerated library, including the docking of compounds, plans for synthesis and starting materials needed:
These compounds have gone to Geoff for MD analysis. All thoughts are welcome.
TomkUCL
commented
6 months ago Other semi-relevant points of interest:
AZ just published on a framework for designing combinatorial libraries using a molecular generative model to generate de novo building blocks using open source software https://doi.org/10.1039/D3DD00095H https://github.com/SeemonJ/combinatorial-library-design-dpp
Nucleotide analogues that exhibit some viral helicase selectivity.
Ring-Expanded (“Fat”) Nucleoside and Nucleotide Analogues Exhibit Potent in Vitro Activity against Flaviviridae NTPases/Helicases, Including Those of the West Nile Virus, Hepatitis C Virus, and Japanese Encephalitis Virus:
https://pubs.acs.org/doi/epdf/10.1021/jm030842j
Date: Monday 11th Dec 2023 Time: 5pm GMT (other times) Place: https://ucl.zoom.us/j/97172937586 Previous meeting recordings: https://www.youtube.com/@MedChemCoreD-UCLSoP Previous Meeting Issue: https://github.com/StructuralGenomicsConsortium/CNP4-Nsp13-C-terminus-B/issues/42
Who can come?: Anyone. No need to say anything unless you'd like to. If you'd like to contribute to these meeting issues, please join Github.
Attending: Team can be seen at https://github.com/orgs/StructuralGenomicsConsortium/teams/cnp4-nsp13
Slide decks: Please https://github.com/orgs/StructuralGenomicsConsortium/teams/cnp4-nsp13 remember that if you share slides/info, drag and drop those into a comment on this page, below. Very easy and saves @mattodd having to pester you.
Key Things This Month (please add if you'd like to focus on something):
Agenda and Actions Arising:
@TomkUCL update on mini-virtual screen of fixed core1; https://github.com/StructuralGenomicsConsortium/CNP4-Nsp13-C-terminus-B/issues/43 need to confirm with @kipUNC that none of these compounds are present in the previous Enamine REAL 34B screens.
Jelena to update on nsp13 protein production at UCL for NMR and GCI biophysical assays.
@ahsgc to maintain contact with Piramal re building block completion and delivery to UCL <-- all complete?
ATP-periodate remains the best control we have. @alvaro-magalhaes has shipped the lit indole compounds first identified by @jamesday100 (now published) https://github.com/StructuralGenomicsConsortium/CNP8-Nsp13-Indoles
Are there any CACHE competition compounds (designed vs the RNA-binding site) that can be used as a comparator, or as a source of potential control compounds? Or as a source of a machine-learning model that could be used to predict better binders in a second round?
@TomkUCL has used UCL's Creoptix wave to evaluate all local UCL compounds. Data arising? (No control protein was being used. Toronto has used WDR5, UCL could use carbonic anhydrase, etc. Alignment could help publishing the work!)
Structures
AOB
@jamesday100 had raised the question of whether we should go back and examine the other sites highlighted in the original fragment screen. @kipUNC mentioned that compounds were designed, purchased and evaluated vs ATP- and RNA-binding sites. @kipUNC to dig up the data.
@jamesday100 has indicated he'd like to step down as pharma champ, so it would be very good if there were another pharma champ willing and interested to come on board, perhaps with more general interest in Nsp13 and helicases.