Submission Details

Design Rationale:

The design exploits the cyclopropyltriazole P1 substituent of x10324. Attempting to use the NH of secondary amides, like the x10324 ligand, as a synthetic handle is likely to ‘flip’ the amide geometry from trans to cis as detailed in these notes (the cyclization locks the amide geometry and prevents it from ‘flipping’): https://doi.org/10.6084/m9.figshare.12440486.v1 Cyclization increases the area of contact with the molecular surface of the protein and creates a number of options for access to the active site. Specifically, this scaffold presents vectors for targeting both the catalytic cysteine (e.g. with a warhead such as nitrile) and imidazole. For modelling, I’ve used the configuration (S) that enables the designed ligand to more effectively align with the ligand in the x10324 crystal structure although an assay result for the racemate would also provide useful information for decision making. I’ve uploaded pdb file with the designed structure as it is predicted to bind to the protein in the x10324 crystal structure.

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