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StructuralGenomicsConsortium / CNP25-CHIKV-nsP3-Macrodomain

This project aims to develop a chemical probe of CHIKV-nsP3-macrodomain starting from a fragment screen
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Can we fork towards covalent binders? #6

Open rahmanszsaleem opened 2 months ago

rahmanszsaleem commented 2 months ago

Upon obtaining the crystal data of the merges, we have been analyzing PyMol sessions for a potential site for covalent modification. The analysis seems to suggest Cys34 could be an interesting residue to target by modifying merged compounds or by exploring a library of electrophilic compounds. Thr111 is also an interesting site for such modification.

The bigger question: What type of modification would you suggest to these merges to convert these into covalent binders?

The screenshots are given below

x2343 has Cys34 pointing towards the merge (and Cys143 point away) image

similar is the case with x2346 image

view of x2350 also shows potential of cys34 image image

X2364, again Cys34 seems interesting image image

In x2352, OH-group on Thr111 may be interesting: image image

jasminaschenbrenner commented 2 months ago

I haven't seen the Cys143 ever point into a different direction than away from the ADPr-binding site as you see in the snapshots, so I am not sure if it would be accessible for a covalent modification? I am still learning this, but not every cysteine can be targeted because it also depends on the local chemical environment around it. Do you think the suggested Cys are suitable?

rahmanszsaleem commented 2 months ago

What do you think about Cys34 and Thr111? Also, are any other Cys/Thr/Lys suitably located for targeting with covalent modifications of the merges?