This project aims to develop potent inhibitors of NSP14/NSP10 for the treatment of (CoV-19), Targeting the NSP14 and NSP10 interacting interface with small molecules or peptides could be a smart strategy to obstruct replication processes of coronaviruses (CoVs).
1
stars
0
forks
source link
Community Design of Grown/Merged/Linked Fragments vs Nsp10/14 Interface #6
We need help with the design of new small molecule binders of SARS-CoV-2 Nsp10/14. As outlined on the wiki, we are starting with fragments that have been found to bind the interface between Nsp10 and Nsp14. We would like to improve these (make them better binders). We don't care how we do this - we can grow, merge or link fragments, and we can use human design or automated methods.
Whatever you predict needs to be accessible commercially, or easily through synthesis. We have funds to buy molecules, if they are available from e.g. Enamine Real or another similar vendor. Or if people would like to synthesise candidates, we will test anything you contribute to the project.
The best way to view the fragments is on Fragalysis, specifically here.
We have taken the 18 fragments and clustered them. We are focussing on the pocket with the most fragments bound - Cluster C and maybe the adjacent Cluster B.
Do we have the clustering right? Are we focussing on the best cluster?
Have at it!
Some Possibilities
An example pair of fragments we might want to consider is 10 and 11:
...but there are other possibilities. Fragments 4 and 9 overlap, but maybe we could just grow fragment 4.
Fragment 15 and 18 are good - maybe we need 18 plus an added carbonyl, but maybe we can also include a methylene from 12?
Fragments 9 and 17 look like they could be linked, and maybe to 4 also?
Fragments 10 and 11 also look good for a linking strategy, maybe along with 15?
...but there are lots of other possibilities!
Queries and suggestions: ideally sign up for Github (zero spam) and contribute directly below. Alternatively please reach out by email (chemistry@thesgc.org or Hadia at h.almahli@ucl.ac.uk.
(Static pictures above courtesy of a UCL MPharm student who wrote an early thesis on this area)
mattodd
commented
4 months ago 
rahmanszsaleem
commented
2 months ago
We need help with the design of new small molecule binders of SARS-CoV-2 Nsp10/14. As outlined on the wiki, we are starting with fragments that have been found to bind the interface between Nsp10 and Nsp14. We would like to improve these (make them better binders). We don't care how we do this - we can grow, merge or link fragments, and we can use human design or automated methods.
Whatever you predict needs to be accessible commercially, or easily through synthesis. We have funds to buy molecules, if they are available from e.g. Enamine Real or another similar vendor. Or if people would like to synthesise candidates, we will test anything you contribute to the project.
The best way to view the fragments is on Fragalysis, specifically here.
We have taken the 18 fragments and clustered them. We are focussing on the pocket with the most fragments bound - Cluster C and maybe the adjacent Cluster B.
Do we have the clustering right? Are we focussing on the best cluster?
Have at it!
Some Possibilities
An example pair of fragments we might want to consider is 10 and 11:
...but there are other possibilities. Fragments 4 and 9 overlap, but maybe we could just grow fragment 4.
Fragment 15 and 18 are good - maybe we need 18 plus an added carbonyl, but maybe we can also include a methylene from 12?
Fragments 9 and 17 look like they could be linked, and maybe to 4 also?
Fragments 10 and 11 also look good for a linking strategy, maybe along with 15?
...but there are lots of other possibilities!
Queries and suggestions: ideally sign up for Github (zero spam) and contribute directly below. Alternatively please reach out by email (chemistry@thesgc.org or Hadia at h.almahli@ucl.ac.uk.
(Static pictures above courtesy of a UCL MPharm student who wrote an early thesis on this area)