JHullaert

Some screenshots to clarify the rationale for these designs:

I’m a synthetic organic chemist and only have limited experience with docking, so it would be very nice if a computational chemist could take these designs into his docking calculations! I can also help with synthesis planning for other peoples designs if requested.

1 reply

pgz

I’m skeptical simply switching the warhead and keeping the piperazine will do since the acrylamide warhead is “longer” than the Cl-acetamide. But I see you adressed that with the azetidines in your designs which should give the same N-N angle - really nice idea.

1 reply

JHullaert

thanks! That was indeed where the idea came from to explore piperazine bioisosteres.
Maybe covalent docking could be a way to visualize if the conformational freedom of the cystein residue combined with that of the ligand is sufficient for binding of the piperazine acrylamide.

JAN-GHE-641

Is a similar library based on the melatonin analogue fragment, with even more simplified synthesis.

JHullaert

Summary of compounds I think are most promising and easy to prepare in ~3 to 4 steps from my submissions:

JAN-GHE-641-2 and JAN-GHE-641-10
JAN-GHE-bf4-7 and JAN-GHE-bf4-10 (via mannich reaction)
JAN-GHE-fd8-7 as covalent inhibitor (from 5-Cyano-2-fluorobenzoic acid)
JAN-GHE-1d9-6 as covalent inhibitor

From other peoples compounds, I really like the SEA-xxx compounds, maybe also as fluoroacetamides or acrylamides instead of chloroacetamides.

Big congrats to the organizers, fragment based discovery is really an exciting way of drug design! Looking forward to see what designs have been send to enamine for synthesis.

1 reply

mc-robinson

Thanks for pointing these out! With so many submissions, it is very nice when people condense their favorite ideas, and especially nice when they point of the good ideas to others.

We will get you that info soon. A bit overwhelmed by the amount of submissions and info right now, but we should have it condensed soon.

JoostU

Nice idea to get these screenshots, gives a lot of insight. As to the design, I think it is hard to know exactly from modelling what warhead would fit best, as in my experience, fragments can have quite flexible orientations, once modified. But I like these ideas and the azetidine is very creative, certainly worthwhile trying.