Submission Details
Molecule(s):
Cn1c(=O)c(-c2cc[nH]c(=O)c2)cc2ccccc21
Cn1c2c(cc(-c3cc[nH]c(=O)c3)c1=O)CCCC2
Design Rationale:
The molecule was designed based on non-covalent fragments and was an attempt to see if a quinolone or quinolone-like scaffold may be able tho fit in the active site and interact both with the Glu166 backbone and the P2 pocket (see attached PDB). The pyridine moiety is expected to insert in the P1 pocket. The design was tested by docking, MD and FEP. An IC50 of ~100 uM was measured for the two designs.
Other Notes:
The compounds were synthesized and found to have an IC50 of ~100 uM against cleavage of a fluorogenic substrate. This scaffold may be improved by trying different substituents for the pyridone or different substituent on the quinolone nitrogen. Adding a methyl group at position 7 abolishes binding (IC50 > 160 uM). We'll be happy to provide experimental data and synthetic routes for these molecules.
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