I would like to bring to this discussion comparison between approaches targeting different binding sites, especially when comparing docking/FEP scores.
A very common Mpro inhibition approach is to target the protease activity pocket near the cys-his diad. I can see most proposals are in this region, and therefore it makes sense to compare docking/FEP scoring schemes.
However, there are other important regions that affect protease activity. The dimeric interface between the two termini regions is critical for dimerization and protease activity. Mutations in the termini regions of Mpro of SARS-CoV-1, e.g. Arg298Ala, have shown shift in dimer/monomer equilibrium. And there is also a potentially reactive cysteine there that could be explored for covalent fragments (Cys300).
I submitted non-covalent and covalent proposals targeting these sites.
Covalent: https://covid.postera.ai/covid/submissions/649f4ed0-cf6b-4291-9d7a-5f598e2141d7
Non-covalent: https://covid.postera.ai/covid/submissions/066c4001-b6a3-47b7-83a4-5e7933997959
My question is more related on how this binding site is being looked at by the scientific community (not necessarily for this challenge, but overall). I can’t find much literature on this and I’d appreciate to hear insights