First expansion
2023-11-02
Based on the initial results, compound RA-2923 was the focus of our first expansion set; the compound exhibit good DENV2 Rdrp activity, and shows the least interaction with human mitochondrial RNA production.
For the first expansion set we decided to purchase compounds (via MolPort) that can provide insight on what is important for binding via:
- Truncation: removing separate parts of the molecule
- Scrambled: swapping the molecules moieties around
- Replacement: exchange subunits in the molecule
- Elongation: making the molecule larger (keeping flexibility)
- Conformation: locking part of the molecule through cyclisation, fixating the moieties in a specific orientation
The 12 compounds selected are outlined below.
2024-01-26
In early January the 12 compound expansion library based on RA-2923 were tested in the DENV2 picogreen assay. Unfortunately a majority of the compounds were not active. It seems the cyclopropyl is important to binding as replacing this (as in RA-9741) produced an inactive compound. Similarly, truncating the RA-2923 and removing the cyclopropyl-oxadiazole generated an inactive compound (RA-9746). It seems the methoxy-benzene moiety is less important for binding, as removing or replacing it in RA-9742, -9743, -9744 retained some activity (4-6 fold reduction in activity).
- Expanding on RA2923 was paused while we try to identifying a better starting point