Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/NIM-UNI-13494739
For these dihydropyrazole analogues, is there a reason for having an sp3 centre on one side? Could you not have another double bond or is there a stereochemical justification?
Would a nutlin (cis-imidazoline) analogue be a suitable, more “synthesisable” option?
I based this submission on MAT-POS-916a2c5a-1 which has the best IC50 value so far and were other dihydropyrazoles in REAL space. MAT-POS-916a2c5a-1 itself was based on hits from the original SAR-CoV protease https://pubchem.ncbi.nlm.nih.gov/bioassay/1890. I wrote this in my design rationale. I don’t know why this hasn’t come through.
I’d be surprised if some pyrazoles hadn’t been screened in the original fragment screening. Unfortunately we don’t know what was screened and didn’t come up active. Would be useful information to have.
1 Like
Thanks, Nimesh. Let me work on getting that info in a more easily readable way, it should be present from the inhibition data here https://covid.postera.ai/covid/activity_data (all those with low inhibition at 50 uM), but obviously is not clear. I assume you are also wondering about those that were screened crystallographically and din’t bind in the original fragment screen?
Thanks, it’s a lot clearer to see that information now. I’m not personally wondering about non-active structures in the original fragment screen because my view is that common scaffolds will have been screened and the focus should be on the hits that were identified. However, it would be useful to have these as a filter so you don’t end up synthesising and testing submissions that is already known to be inactive.