Submission Details
Molecule(s):
CNC(=O)CN1C[C@]2(CNC(=O)N(c3cncc4ccccc34)C2=O)c2cc(Cl)ccc2C1=O
CNC(=O)C1(N2C[C@]3(CNC(=O)N(c4cncc5ccccc45)C3=O)c3cc(Cl)ccc3C2=O)CC1
CNC(=O)CN1C[C@]2(CCC(=O)N(c3cncc4ccccc34)C2=O)c2cc(Cl)ccc2C1=O
CNC(=O)C1(N2C[C@]3(CCC(=O)N(c4cncc5ccccc45)C3=O)c3cc(Cl)ccc3C2=O)CC1
CNC(=O)CN1CC2(CNC(=O)N(c3cncc4ccccc34)C2=O)c2cc(Cl)ccc2C1=O
CNC(=O)C1(N2CC3(CNC(=O)N(c4cncc5ccccc45)C3=O)c3cc(Cl)ccc3C2=O)CC1
CNC(=O)CN1CC2(CCC(=O)N(c3cncc4ccccc34)C2=O)c2cc(Cl)ccc2C1=O
CNC(=O)C1(N2CC3(CCC(=O)N(c4cncc5ccccc45)C3=O)c3cc(Cl)ccc3C2=O)CC1
Design Rationale:
The four designs in this submission combine two spirocyclic fusions (dihydrouracil; glutarimide) of the dihydroisoquinolone scaffold with two pendant amide substituents on the DHIQ nitrogen. I consider dihydrouracil/glutarimide (6-membered rings) as more likely to be able to accept a hydrogen bond from G143 than their hydantoin/succinimide (5-membered rings) analogs. The four designs 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) [3-6] Binding modes predicted for Designs 1-4.