Submission Details
Molecule(s):
O=C(Cc1cccc(Cl)c1)Nc1nnc2ccccn12
Design Rationale:
This design is derived from PET-UNK-8df914d1-2 which is an order of magnitude less potent than the isoquinoline analog ADA-UCB-6c2cb422-1. One rationale for the difference in potency between the two inhibitors is that the geometry of the hydrogen bond that aza nitrogen accepts from H163 is more optimal for ADA-UCB-6c2cb422-1 than for PET-UNK-8df914d1-2. Under such a scenario, aza substitution next to the nitrogen that accepts the hydrogen bond might stabilize the hydrogen bond at the non-ideal geometry (lone pair repulsion means that the optimal HB donor position may be off the lone pair axis).