Submission Details

Design Rationale:

The molecule was build based on previous non-covalent inhibitor. The 3-cyano pyridine moiety is an acceptor for the backbone hydrogen bonds from Glu 166 and Gly 143. The quinolone group is fitting in the P1 pocket, while the T-buthyl group inserts into the hydrophobic P2 pocket (see PDB file). The design was tested against docking, MD simulations and FEP. We experimentally measured an IC50 of 32 uM.

Other Notes:

This compound has been synthesized and an IC50 of 32uM was measured against cleavage of a fluorogenic substrate. Removal of the T-butyl group results in an inactive compound (IC50 > 160 uM). This was our first shot at this scaffold and we believe that there is plenty of room for optimizing this scaffold by trying different substitutions for the Quinolone and T-buthyl groups. It may also be possible to add a further functional group at C5 on the pyridine ring, but this will probably complicate the synthesis. Solubility should be carefully taken into account in future designs as this molecule has a solubility of ~50 uM. We'll be happy to share raw experimental data or synthetic routes.

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