Submission Details
Molecule(s):
COC[C@@]1(C(=O)Nc2cncc3ccccc23)CN(S(=O)(=O)CC2(C#N)CC2)C(=O)c2ccc(Cl)cc21
C#C[C@@]1(C(=O)Nc2cncc3ccccc23)CN(S(=O)(=O)CC2(C#N)CC2)C(=O)c2ccc(Cl)cc21
COCC1(C(=O)Nc2cncc3ccccc23)CN(S(=O)(=O)CC2(C#N)CC2)C(=O)c2ccc(Cl)cc21
C#CC1(C(=O)Nc2cncc3ccccc23)CN(S(=O)(=O)CC2(C#N)CC2)C(=O)c2ccc(Cl)cc21
Design Rationale:
This submission is related to PET-UNK-7955f415 (pendant amide substituent on dihydroisoquinolone nitrogen is replaced with 1-cyanocyclopropylmethyl). The two designs in this submission are intended to both lock the configuration of the chiral center and to address potential efflux associated with the amide NH. Each configurational lock features a bond between a carbon atom and the chiral center (my understanding is that the methoxy-locked dihydroisoquinolones tend to eliminate methanol to form the corresponding isoquinolones). The conformational locks are designed to address efflux by restricting access of the amide NH to transporter recognition sites. Design 1 (methoxymethyl) uses an intramolecular hydrogen bond to hide the amide NH. Design 2 (acetylenyl) is intended to make it more difficult for the amide NH to interact with a hydrogen bond acceptor from a transporter that might be the cause of active efflux. Both designs present opportunities for exploiting the S1’ region of the binding site. Each design has also been submitted as a racemate.
Other Notes:
Protein-ligand complexes (P1788 A chain) were energy-minimized using Szybki (MMFF94S) fixing the coordinates of the amide nitrogen and oxygen. 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] Binding mode predicted for ALP-POS-c56c1477-3 [4-5] Binding modes predicted for Designs 1 -2.