pgz

Hello Nimesh,

some of the fragments (e.g. x1386) you used as inspiration were from the covalent set. In your designs, there is no electrophile to react with a proximal Cys. I would suggest re-attaching the Cl atom to your N-acetyl groups to keep the covalent binding mode, which delivers a significant part of “affinity”.
It can be hard to detect the covalents since the bond is not explicitely modeled in.
Using the following link you can download the set of covalents where you need to work back the electrophile back into your designs.

https://www.diamond.ac.uk/dam/jcr:201d639f-ed89-4e50-82e2-93e00b296c66/Mpro%20full%20XChem%20screen%20-%20pdbs%20-%20covalent%20-%20ver-2020-03-18.zip

Best Regards
Paul

1 reply

mc-robinson

Hi @pgz, thanks for pointing this out… I was just going over this issue myself and noticed that the fragalysis tool shows x1386 like so (with no chlorine):

@AnthonyA, do you know what is going on here? I see that in the Mpro full XChem screen - hits summary - ver-2020-03-18 file the Smiles is modified to go from Compound Smiles of ClCC(=O)N1CCN(Cc2ccsc2)CC1 to Modified Compound Smiles of CC(=O)N1CCN(Cc2ccsc2)CC1. I guess this makes sense since the chlorine leaves, but it is slightly confusing for someone designing the initial covalent inhibitor.

1 reply

AnthonyA

The smiles with truncated Cl atom was for the crystallographers modelling the structures…
Crystallographers know that if you have a compound with an atom really close to protein residue, the coot software will show a dashed bond which can simulate the covalent bond. But this is not obvious with fragalysis yet.
I will probably just remove the column modified smiles string, or comment on it. And add something on the diamond website, that you can duplicate on your website

Nimesh

Hi Paul

Sorry for the slow reply, I’ve only just seen my submissions had an accompanying discussion board.

I did mean to submit my compounds as covalent inhibitors. I thought that you didn’t need to add the chlorine as these weren’t present in the fragments on Fragalysis.

I’ve just seen the call for more submissions by this Thursday, so perhaps the easiest thing for me to do is to resubmit these fragments with the chlorines included.

Thanks for your feedback.

Nimesh

1 reply

pgz

Hi Nimesh,

no worries, glad to hear that.

Best
Paul