Submission Details
Molecule(s):
O=C(NC1CNCc2ccccc21)[C@@H]1CCNc2cc(Cl)c(Cl)cc21
Design Rationale:
John Chodera mentioned that the isoquinoline scaffold may be chelating iron in cytochromes P450. I suggest trying a scaffold hop to a tetrahydroisoquinoline (THIQ), a scaffold found in several marketed drugs. My colleague Hyun-Soon "Joy" Chong is an expert on metal chelation and does not think that THIQ is a metal chelator. She is also an expert on THIQ, having developed a synthetic method for stereoselective synthesis of THIQs at the 4 position. (Coincidentally, she has actually made compounds similar to this lead series.) I also asked a student to perform molecular docking. Her calculations predicted that the THIQ moiety is oriented in the same way as the isoquinoline moiety. Binding affinity may be affected, as nitrogen will need to be a hydrogen bond donor opposed to an acceptor and this will require a rotation of histidine 163. However, she also noticed that histidine 163 flips in the DESRES simulation of MPro, suggesting that the energy of the rotomer is comparable. Hence I predict that the metabolic toxicity will be reduced while maintaining similar affinity.