Submission Details
Molecule(s):
N#CCN1C[C@]2(CC(=O)N(c3cncc4ccccc34)C2=O)c2cc(Cl)ccc2C1=O
C#CCN1C[C@]2(CC(=O)N(c3cncc4ccccc34)C2=O)c2cc(Cl)ccc2C1=O
N#CCN1CC2(CC(=O)N(c3cncc4ccccc34)C2=O)c2cc(Cl)ccc2C1=O
C#CCN1CC2(CC(=O)N(c3cncc4ccccc34)C2=O)c2cc(Cl)ccc2C1=O
Design Rationale:
The two designs on this submission replace the pendant amide of MAT-POS-1bed62cf-3 with cyano and acetylenyl respectively. For P2-tetrahydroisoquinoline the amide NH holds pendant amide in the right orientation by interacting with the neutral tetrahydrohydroisoquinoline nitrogen. However, the corresponding nitrogen of P2-dihydroquinolone is amidic and cannot interact in a similar manner with the pendant amide NH. This submission is based on the design hypothesis that the pendant amide NH is required for P2-tetrahydroisoquinolines but not for P2-dihydroquinolones. It is also noteworthy that the pendant amide does appear to make contact with the protein surface whether it is on tetrahydroisoquinoline scaffold or dihydroquinolone scaffold (effects on potency appear due to contact with the P2 heterocycle. My recommendation would be to synthesize PET-UNK-aa57768f-1 ahead of either design in this submission. The racemates for the designs have been included in this submission.
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) [3-4] Binding modes predicted for Designs 1-2.