Submission Details
Molecule(s):
N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3[C@@]3(CCC(=O)N(c4cncc5ccccc45)C3=O)C2)CC1
N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3[C@@]3(CNC(=O)N(c4cncc5ccccc45)C3=O)C2)CC1
N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3[C@]3(C2)OCC(=O)N(c2cncc4ccccc24)C3=O)CC1
N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3C3(CCC(=O)N(c4cncc5ccccc45)C3=O)C2)CC1
N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3C3(CNC(=O)N(c4cncc5ccccc45)C3=O)C2)CC1
N#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3C3(C2)OCC(=O)N(c2cncc4ccccc24)C3=O)CC1
Design Rationale:
The three designs in this are six-membered analogs of the spirocycle LUO-POS-868e8996-9 (50 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 (P1788 A chain) were energy-minimized using Szybki (MMFF94S). The PDB file associated with this submission contains the following: [1] P1788 A chain protein structure [2] P1788 A chain crystallographic ligand (MAT-POS-dc2604c4-1) [3-5] Binding modes predicted for Designs 1-3.