PostEra

Choice of Covalent Warheads

COVID Design
#1

The vast majority of the covalent bound ligands in the Diamond crystal structures use NC(=O)CCl as the warhead. There are a few examples with C#CBr and probably a few others for which the SMILES has been transformed so its difficult to identify the warhead by eye.

I’m about the embark on some large scale virtual screening for covalent ligands (as well as docking the submissions and redocking crystal structures).

On the assumption that others have already scoured the relevant literature, it would be interesting to have suggestions about other warheads with or without proof of concept by crystal structures ideally of cysteine proteases (not necessarily Coronavirus proteins) or experiment.

#2

Thanks @EKDavies, obviously a very interesting issue since – to the best of my knowledge – there are still no approved covalent cysteine protease inhibitors ( Odanacatib made it to phase 3). I know there was some discussion in A brief exploration of past SARS small-molecule inhibitors . I will also mention that practically all of the current Ugi hits are acrylamides.

#3

there are ots of RSH covalent inhibitors of Cys residues forming disuphide bond, (lanzaprole etc) e.g. proton pump, ADP. I know, it’s not the same but if we could incorporate a SH, prodrug thereof, might be a way forward.
Let’s see how our plavix series gets on!!