Additional information for PET-UNK-c9c1e0d8 submission

I was trying to update the PET-UNK-c9c1e0d8 submission with refined dockings and I got caught out by the three reply rule (consider letting people know about this rule before they compose their messages?). Here’s the text of the message that I had composed:

I have re-docked the two lactams ( PET-UNK-c9c1e0d8-3 and PET-UNK-c9c1e0d8-4 ) in this submission using hybrid and refined the poses using sybki (software from OpenEye). Poses for the two lactams are shown below with the crystallographic ligand (colored in a rather lurid hue) and the molecular surface of the protein has been colored by curvature.

6-ring (this is currently my preferred ligand because it appears to provide better access to the catalytic cysteine)

5-ring

Here is the docking which includes the crystallographic ligand: lactam_docking_1.pdb (449.5 KB)

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Hi @pwkenny, sorry about that. That is a new feature discourse has that I did not know about. I’ve upped the number of allowed consecutive replies to 7 – so hopefully no longer an issue.

Thanks for the docking! We’ve had a bit of trouble with synthesis regarding the cyclization compounds, but this is an interesting idea. I know we have the 5 membered ring being made, and hopefully tested soon. Going on your idea though, where would you imagine a warhead accessing the cycsteine on the 6 membered ring?

Hi Matt, right now I see this structure with the nitrile warhead directly attached to the ring carbon as the best option. The 5-membered ring might work better if putting a methylene spacer between the warhead and the ring. I plan to do more docking and will keep you posted. I think that it’d be best to first see how the potencies for the the 5 and 6-membered rings compare with that of the parent compound before attempting to link the warhead.

On a more general theme, I think that it would be worth looking at all the series that are being worked on to assess potential for inclusion of a reversible warhead (I would guess that this tactic could work well for the Ugi compounds). I would generally use nitrile as the default reversible warhead but there are other possibilities. This article on warheads may be helpful (apologies if I’ve already shared it).

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