pgz

Hello Jan,

first of all - thanks for your contribution. x1386, one of your inspirations, contains a C-S bond resultant from a reaction of a Cys with a Chloroacetamide. It would be a good idea to re-install the electrophile into your N-acetylpiperazine-type designs where appropriate (proximal to Cys). If you want some more background info, there are a few other threads on here which go into more detail.

Best
Paul

2 replies

JoostU

Ai. I think I made this mistake as well. Will resubmit - best Joost

JHullaert

Dear Paul,

Is there any way to modify my two submissions to the corresponding chloroacetyl piperazines?
Seems like I can’t edit them myself, or should I resubmit?

Thanks!

1 reply

mc-robinson

Hi unfortunately, since we did not force people to make accounts, there is no edit functionality. So please do resubmit! I can add a note to the original saying that some or all of the compounds have been changed in the new submission.

Sorry for the inconvenience – this is one of the many issues that make me regret my choices when hacking away to build the site very quickly.

JoostU

Hi,

I resubmitted JOO-PER-b26 and JOO-PER-7ae yesterday evening, but they don’t show up. Is there some glitch?

best Joost

1 reply

mc-robinson

Hi,

I see them here:

https://covid.postera.ai/covid/submissions/7aee54b6-c8af-47a0-9885-6788bff11b6a
https://covid.postera.ai/covid/submissions/b262154b-b040-4e71-a9df-a65bb328bdaa

Note that the submissions do not show up in order of submission, sorry for that

1 reply

JoostU

Hi,

Thanks for the reaction. These are the old molecules. I resubmitted them with a chloroacetamide warhead, but can’t find the new entries. Maybe I should resubmit the resubmission?

best Joost

1 reply

mc-robinson

Ahh I am not sure what is going on there, sorry! Let me delete your current two submissions and then have you resubmit the new ones.

So please go ahead and try to resubmit – let me know if you have any further issues!

By the way, I saved your text in case you dont want to rewrite it…

Overlay of fragment 0830 with 0104. Nr. 0830 presents the methylketone piperazine scaffold that is seen in many fragments and which binds covalently to Cys 145. Nr. 0104 has a flexible chain that addresses a backpocket with some nice interactions a.o to Glu 166 and Gln 189, and replaces some crystal waters seen in the complex with 0830. If this works, flexibility in the 0104 can maybe be reduced for better affinity. Also the warhead that binds to Cys 145 needs to be replaced with a more drug-like one.

There is a family of fragments including 0692, 0830, 0770 and 1386 that contain a methyl keton warhead followed by a piperazine scaffold. This is a modification of fragment 0830 incorporating a chloride from 0770 that protrudes deep into a back pocket near Asp 187. It also incorporates a nitrogen to make contact with Gln 169, nice sandwiching the ring into this pocket. If this works, this molecule can be elaborated on, including changing the warhead for a more drug-like one, and even better addressing the pocket through extra substitutions.

1 reply

JoostU

Thanks for saving the text! I resubmitted and now they appear in the collection, so all’s well.
best Joost