Submission Details
Molecule(s):
CNC(=O)CN1Cc2ccc(Cl)cc2[C@@]2(CCC(=O)N(c3cncc4ccccc34)C2=O)C1
CNC(=O)CN1Cc2ccc(Cl)cc2[C@@]2(CNC(=O)N(c3cncc4ccccc34)C2=O)C1
CNC(=O)CN1Cc2ccc(Cl)cc2[C@]2(C1)OCC(=O)N(c1cncc3ccccc13)C2=O
CNC(=O)CN1Cc2ccc(Cl)cc2C2(CCC(=O)N(c3cncc4ccccc34)C2=O)C1
CNC(=O)CN1Cc2ccc(Cl)cc2C2(CNC(=O)N(c3cncc4ccccc34)C2=O)C1
CNC(=O)CN1Cc2ccc(Cl)cc2C2(C1)OCC(=O)N(c1cncc3ccccc13)C2=O
Design Rationale:
The three designs in this are six-membered analogs of the spirocycle LUO-POS-868e8996-7 (120 nM) in the enzyme inhibition assay. The design hypothesis is that the second carbonyl in a six-membered ring will be better able to interact with the oxyanion hole than when in a five-membered ring. I see Design 1 (glutarimide) as the highest priority although Design 2 (dihydrouracil) may also be of interest because the imidic carbonyl oxygens will be stronger HB acceptors than their Design 1 equivalents. Design 3 is the morpholinedione analog of Desigh 1 (replacement of CH2 with O will reduce lipophilicity and might also help with synthesis). The three designs in this submission have also been submitted as racemates.
Other Notes:
Protein-ligand complexes (P1090 A chain) were energy-minimized using Szybki (MMFF94S). The PDB file associated with this submission contains the following: [1] P1090 protein structure [2] P1090 A chain crystallographic ligand (MAT-POS-4223bc15-23) [3-5] Binding modes predicted for Designs 1-3.