Thread by @GahbauerStefan

Thrilled to share our preprint on structure-based discovery and optimization of SARS-CoV-2 macrodomain (Mac1) inhibitors. We present several low- to sub-micromolar inhibitors and atomic SAR thanks to >150 crystal structures!
biorxiv.org/content/10.110…

Super proud and grateful to be part of an amazing team including scientists from the @BShoichet @fraser_lab @IvanAhelLab @Ashworth_SF @GestwickiLab @adamrenslo @chem4biology and @FrankvonDelft labs!

BIG shoutout to Galen (@fraser_lab) for soaking roughly 300 molecules and determining many many many many crystal structures at 1 Å resolution. All of which are about to be released in the PDB @buildmodels and fragalysis.diamond.ac.uk (Thanks @Darenfearon)

Following our previous fragment screens (science.org/doi/10.1126/sc…), we used @matteoferla's fragment-linking tool Fragmenstein (github.com/matteoferla/Fr…) and designed identified a potent scaffold bridging different subsites. (Video by Galen)

In addition, we performed ultra-large library docking of more than 450 million molecules to identify additional compound families exploring different interaction patterns with Mac1.

We also found some unexpected protein dynamics within the catalytic site of Mac1 in the crystal structures for a handful of compounds. Perhaps offering novel pockets for small molecules design? (Video by @fraser_lab)

Structure-based optimization of initial hits was guided by in-solution binding experiments performed by Yagmur and Morgan (@Ashworth_SF lab), @_MarionSchuller and @taiawu.

And finally, a huge acknowledgement goes to our colleagues at @enamine and @chemspace for making ALL molecules for this work.

There is still lots to do for developing potential antiviral therapeutics targeting Mac1 and we hope our study accelerates efforts throughout the community! #compchem #CADD #drugdiscovery

Whoops, messed up some shoutouts. @EnamineLtd and @Chem_space made all molecules for us! Can't stress their impact on this work enough.