Submission ALP-POS-c59291d4

Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/ALP-POS-c59291d4

@JSPEN, @miko_a, @nnarvaiss, and others who submitted designs based on ALP-POS-c59291d4-5.

We now have an initial crystal structure and this indeed acting as a covalent inhibitor. From the very initial structure, the density of the indole bound to the cysteine does not seem to be that well defined; thus, we are skeptical of pursuing it any further.

Some of the other chemists seem a bit surprised that this ester is such a “hot electrophile,” but it seems that its strength is mostly from that.

Hi.
To be fair this binding is at the catalytic site and it is a lot easier to hydrolize esters than amides (especially phenol-type esters). The low IC50 values could be explained due to favourable interactions in initial non-covalent complex. It would seem quite reasonable to try a secondary (NH) or tertiary (NMe) amide analogues as they would have similar initial complex/geometry, but no covalent interactions.

Does the skepsis of working on this scaffold comes from predicted poor ADME or selectivity issues?

While it might not make a good drug - reporting on these esters could be useful for people looking to develop new synthetic reactions

Hi Matt,

The aza and meta-chloro substituents will both make the chloropyridine a better leaving group relative to phenyl. I would anticipate issues with both selectivity and in vivo stability for this (and similar) compounds.

Thanks @nnarvaiss, @pwkenny, @stentor,

As Peter points out, main concerns are selectivity and stability given how reactive it is. @nnarvaiss I guess making the amide is in an interesting way to probe if any of the good binding is a result of favorable non-covalent interactions.

-Matt

@nnarvaiss @stentor @mc-robinson Just a quick point of clarification to correct an error on my part. The leaving groups are actually 3-chloro, 5-hydroxypyridine and phenol rather than chloropyridine and phenyl. Apologies for any confusion.

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