AnthonyA
@mc-robinson, Daren will release a structure for this one. Was is designed knowing it had a covalent warhead?
It dont think it has any covalent flags, and I certainly missed it when looking at the shipment, so no flags on CDD either
@mc-robinson, Daren will release a structure for this one. Was is designed knowing it had a covalent warhead?
It dont think it has any covalent flags, and I certainly missed it when looking at the shipment, so no flags on CDD either
Tagging @Daren_Fearon in thread as he did the refinement work
It required co-crystallisation to get the structure too so possibly less reactive that other warheads?
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Hi @Daren_Fearon and @AnthonyA, what specific ID is this? Sorry it’s confusing that the comment is associated with the whole submission.
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MAT-POS-fa06b69f-6 - on Fragalysis as Mpro-x11894
This is structurally related to the ene-rhodanines that cause PAINS filter advocates to spit feathers (and may even match a PAINS substructure). I would recommend (as I would for any structurally-novel hit) that you check reversibility, assess interference with readout and examine the concentration response carefully before committing resource to following up this hit. The reversibility check is i particularly important because it is not meaningful to compare IC50 values for reversible and irreversible inhibitors. In case it’s of interest, I have argued that the PAINS filter rhetoric is not actually supported by the data.
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Thanks @pwkenny, it does indeed match that PAINS substructure as shown in the alerts here https://postera.ai/manifold/68b7d5c9-2dff-4eb1-b5bd-23da1dbf1c72/0/
@AnthonyA and @Daren_Fearon, that Michael acceptor must not have been caught by our covalent warhead, which cover more the “canonical warheads” in covalent drug discovery.
Given the “unattractiveness” of this hit (take that as you will), and our current focus on covalent compounds, I think this one was left behind.