The Story So Far

The starting point for the project is the dataset derived from a fragment screen vs the macrodomain carried out at the Diamond Light Source by Daren Fearon and Jasmin Aschenbrenner in late 2023. The data are being refined (January 2024).

The aim of the project is to use these fragments to design a chemical probe binding to the CHIKV nsp3 macrodomain, particularly to ADP-Ribose site in where the substrate binds and where the active site residue(s) are located. This enzyme is a promising antiviral target because catalytic mutations render viruses nonpathogenic 1, 2, 3. By finding molecules with high affinity for this site, the substrate wouldn't be able to bind and no reaction would occur.

Here are a few fragments have been identified so far by DLS team in nucleotide binding site of CHIKV nsp3 macrodomain: The images taken from our collaborator (DLS team) presentation.

Using Fragmenstein and Knitwork generated various sets of merged compounds binding to different sits of the protein target, see the following picture:

You can also see other few fragments which have also been identified by DLS team in different sites of CHIKV nsp3 macrodomainTarget meeting's slides-7 Dec 2023

A kick-off meeting was held Feb 5th 2024 to discuss the compounds screening and triage. The UCL team visited Diamond house on 22nd March 2024 to discuss the possibility to use the DLS tools for Fragment merged compounds design, the agreement took place and the curation of several compounds sets was carried out and led to nominate 85 compounds for purchase see here from REAL-ENAMINE on 24th April 2024 and to be shipped to Diamond for testing. 354 compounds were shortlisted for RAC.

On 15th April 2024, the DLS team visited us at UCL to discuss different aspects of the project, particularly the automated chemistry for a big number of analogues to be done in Diamond house.