Given recent interest in the tetrahydoisoquinoline-based scaffold (in particular, the methylsulfonyl analog MAT-POS-dd3ad2b5-4), it may be helpful to share some observations on protein structures for chromane-based ligands. The IC50 for MAT-POS-dd3ad2b5-4 does not to appear to have been uploaded (at least the last time I checked) and I’m assuming, based on notes associated with the FRA-DIA-6238d354 submission, that it is about 100 nM. I’ll mention @alphalee @frankvondelft @JohnChodera @londonir @mc-robinson @edgriffen in case these observations are of interest.
The puckering of the chromane ring appears to differ according to whether or not the configuration of the chiral center has been ‘locked’ by quaternization. This can be seen in a graphic showing the crystallographic ligands from X11612 (crystallographic ligand: MAT-POS-b3e365b9-1 ; ‘unlocked’ configuration) and X12207 (crystallographic ligand: EDJ-MED-e4b030d8-13; configuration ‘locked’ by methyl substituent).
Sulfonamide nitrogen is typically pyramidal and the C-S tends to be anti with respect to the nitrogen ‘lone pair’. Here’s a graphic showing predicted bound conformations for the S enantiomer of MAT-POS-dd3ad2b5-4 (‘unlocked’ configuration) and PET-UNK-9bf1291a-1 (‘locked’ configuration). ‘Locking’ the configuration makes the S-C vector point in the opposite direction and this has implications for design.