Submission Details

Design Rationale:

Design was done by mixture of docking and manual building with energy refinement. Starting from biarylurea structure Mpro-x0434, the idea was to cyclize to rigidify the urea moiety. This can be done in different ways but the best-looking scaffold seems to be a pyrimidine-2,4(1H,3H)-dione scaffold. It keeps the nitrogens and carbonyl of the urea in place with the carbonyl making a hydrogen bond to Glu166 backbone NH as seen in the original fragment; plus it introduces another hydrogen bind with Gly143 NH. This design is the smallest of the submissions. The next step is to annulate the scaffold with another benzene ring resulting in a Phenylquinazoline-2,4-dione (PAQ) scaffold. This scaffold is described in literature in Nakagawa et al., Bioorganic & Medicinal Chemistry, 16(14) 7046-7054, https://doi.org/10.1016/j.bmc.2008.05.016 although not with a di-aromatic connection. Introducing a Cl or Br in position 7 on the scaffold leads to a halogen bond with Cys44 C=O backbone. Cl is a weaker halogen bond donor than Br so the 6-F is introduced to tune the halogen bond in the case of Cl (can of course also be done with Br).

Inspired By:

AAR-POS-d2a4d1df-11