Submission DAR-DIA-076fb6ea

Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/DAR-DIA-076fb6ea

Hi @Daren_Fearon

I’ll mention @londonir and @frankvondelft since they are interested in covalent inhibition. The design that I see as top priority in this set is DAR-DIA-076fb6ea-1 since it’s structurally prototypical and P1-isoquinoline is associated with higher potency than P1-pyridine.

I think that DAR-DIA-076fb6ea-3 would be worth synthesizing since either carbon of the vinyl group can function as the electrophilic center. You may wish to consider replacing the methoxycarbonyl group with something a bit more ‘compact’ like cyano or CF3.

It may also be worth considering replacing the vinyl group of DAR-DIA-076fb6ea-1 with acetylenyl (I’m guessing more electrophilic and the triple bond may help with transition state geometry).

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Thanks, @pwkenny. I’m also just going to tag @AnthonyA here since he has special interest in the covalent inhibition strategy.

Good thinking, Matt, and I’ll tag him in any any future posts/comments on this topic. There may be value in creating a covalent inhibition design theme to help focus crowdsourcing input.

We’re dividing a lot of this synthetic work on covalent warheads in my lab with Enamine scientists. Watch this space. The usual suspects are being made with a lot of input from my postdoc, Storm Hart, who’s in regular contact with @AnthonyA to maximise outputs and to avoid duplication of tasks.

I’ve submitted the suggestions (DAR-DIA-56cf811e) but will leave it in @AnthonyA and Storm’s capable hands to decide which are worthwhile/what they can fit in with their plans.

Thanks for letting me know, Daren, and I hope something good will come from this.