Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/EDJ-MED-28ec730d
Hi Ed @edgriffen
I would recommend synthesizing & assaying the compounds with the prototypical linkers (either methyl DAR-DIA-6a508060-10 | EDJ-MED-e4b030d8-13 | MAT-POS-8e4737f4-1 or methoxy PET-UNK-29afea89-2 at C4 of the dihydropyran) before attempting to exploit the linkers. This can be thought of as a hit-to-lead version of pruning a decision tree and I’ll also mention @JohnChodera since I’d replied, along similar lines, to one of his tweets on a ‘sprint’ to target the S1’ subsite.
1 Like
Hi Pete, We’ve had success making EDJ-MED-e4b030d8-13 which should be shipping this week. The synthetic route makes the other intermediates look quite feasible. We also have good evidence from the benzotriazole series that overlays well with the benzopyrans that P1’ pocket should be accessible from this vector. If you look in fragalysis, the overlay of the structures x11498 and x10871 look pretty good. We won’t be starting synthesis till we have some concrete data, John’s work is to prioritise the most synthetically accessible options.
Hi Ed, It could be an idea to check with @frankvondelft to see if there has been progress in getting a crystal structure for BEN-DND-93268d01-8. An alkyne spacer (e.g. PET-UNK-29afea89-1 may be more ‘conformationally forgiving’ than alkyl or alkoxy.
BEN-DND-93268d01-8 crystal structure is available (x11417). Similiar isoquinoline compound (ALP-POS-6747fa38-1) has completely different conformation (x11541)
Many thanks for letting me know!
I’ve now had a chance to look at the structures. I’ll mention @frankvondelft so that we can get his input, @edgriffen because I was unaware of the structures in a recent discussion and @Ben_DNDi who synthesized the first of the two inhibitors. I’ll note that the acetamide substructure in X11417 is significantly non-planar (I don’t think it’s particularly relevant to this discussion although it might point to the crystallographic ligand being something other that what it says on the bottle).
The ligand conformation in X11541 is similar to conformations observed in the CSD crystal structures (HODQUP and UWUJAZ ) in which the amidic NH eclipses the lone pair of one of the piperazine nitrogens. While I would expect the basic piperazine nitrogens in both ligands to be unprotonated at neutral pH (my current pKa guesstimate is 5 and I’ll mention @joe since we were discussing this previously), I don’t know whether the crystallographic experiments were performed at the same pH for each ligand. If X11417 was obtained at a lower pH then that could explain the conformational difference between the bound ligands. ALP-POS-6747fa38-1 is barely active (~72 µM in each assay) and BEN-DND-93268d01-8 only shows activity in the fluorescence assay and that should ring some warning bells