The Story So Far
The starting point for the project is the dataset derived from a crystallographic fragment screen vs the Chikungunya (CHIKV) nsP3 macrodomain carried out by Jasmin Aschenbrenner and Daren Fearon from the XChem team at Diamond Light Source in late 2023.
The aim of the project is to use these fragments to design a chemical probe binding to the CHIKV nsP3 macrodomain, particularly to the substrate (ADP-ribose) binding site including the catalytic residues. 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 that have been identified so far by XChem which bind to the adenosine site of CHIKV nsP3 macrodomain: The images taken from our collaborator (XChem 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 Light Source on 22nd March 2024 to discuss the possibility to use the algorithmic XChem tools for follow-up designs via fragment merging. 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 Chemist-assisted Robotics (CAR) which will be done at the Research Complex at Harwell (RCaH).
On 15th April 2024, the XChem 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 at RCaH.
We are now waiting for receiving the Data refinement from the DLS team and the Biophysical assay results.