Submission Details
Molecule(s):
N#Cc1ccc2c(NC(=O)[C@@H]3CCOc4ccc(Cl)cc43)cncc2c1
N#Cc1ccc2c(NC(=O)Cc3cccc(Cl)c3)cncc2c1
N#Cc1cccc2cncc(NC(=O)Cc3cccc(Cl)c3)c12
Design Rationale:
Isoquinoline nitrogen 'communicates' more effectively with C6 than C5, C7 or C8 and the hydrogen bond basicity (and proton basicity) is more sensitive to the effects of substitution at this position than at the other positions. Design 1 of the submission moves the electron-withdrawing cyano substituent of BEN-DND-c852c98b-1 from C6 to C7 with a view to redirecting its effects from the isoquinoline nitrogen to its own ring (reducing electron density with a view to protecting against metabolism). Designs 2 and 3 of the submission substitute ADA-UCB-6c2cb422-1 at C7 and C5 respectively with cyano. The substitution pattern in design 3 is analogous to that in the quinolone MAT-POS-3b536971-1 and may confer similar advantages. Design 3 places the 5-cyano substituent in a position where it may protect the benzylic methylene from metabolism to some extent but this also means that it would be likely to clash with a chromane ring.
Other Notes:
The PDB file contains (1) Protein structure from x11612 (2) MAT-POS-b3e365b9-1 ligand from x11612 (3) Designs 1-3 from current submission. Binding modes for current designs given in pdb file have been energy-minimized (MMFF94S) using szybki (OpenEye