Submission Details
Molecule(s):
Cn1cc(-c2cccc(Cl)c2)c(=O)n(-c2cncc3ccccc23)c1=O
CCn1cc(-c2cccc(Cl)c2)c(=O)n(-c2cncc3ccccc23)c1=O
Cc1ccncc1-n1c(=O)c(-c2cccc(Cl)c2)cn(C)c1=O
CCn1cc(-c2cccc(Cl)c2)c(=O)n(-c2cnccc2C)c1=O
Cn1cc(-c2cccc(Cl)c2)c(=O)n(-c2cccnc2)c1=O
CCn1cc(-c2cccc(Cl)c2)c(=O)n(-c2cccnc2)c1=O
Design Rationale:
Structural variations of PET-UNK-e8933450-1 uracil with combinations of P1 heterocycle (3x) and N-alkyl group (2x). Models built by editing existing model for PET-UNK-e8933450-1 and energy-minimized using Szybki (MMFF94S) from OpenEye.
Other Notes:
I'm assuming that PET-UNK-e8933450-1 will have been evaluated before the synthesis of any of these is attempted. I would anticipate that the potency advantage for isoquinoline over pyridine will less for uracils than for the parent series (e.g. ADA-UCB-6c2cb422-1) on account of the carbonyl groups that flank the P1 substituent. The x10789 crystal structure (ligand: TRY-UNI-2eddb1ff-7) was used for modeling and the protein in the pdb file is from the energy-minimized complex with the first designed ligand. The x10789 crystallographic ligand is included in the pdb file in addition to the 6 designs.