Submission Details
Molecule(s):
N#CCN1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3ccccc23)C1
N#CCN1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3ccc(F)cc23)C1
Design Rationale:
The two designs in this submission consist of two structurally related (the second is a fluoro analog of the first) tetrahydroisoquinolines in which the basic nitrogen is substituted with cyanomethyl. The pKa of aminoacetonitrile is 5.3 ( https://doi.org/10.1021/jo01098a603 ) which should keep lysosomal accumulation under control while preventing secondary pharmacology associated with basic centers. This submission can be seen as a supplement to Ed Griffen's EDJ-MED-009f762b submission.
Other Notes:
The A-chain of X11612 (crystallographic ligand: MAT-POS-b3e365b9-1) was used for modeling (MMFF94S using szybki; N and secondary amide O constrained according to crystallographic ligand). The pdb file associated with the submission contains [1] Protein structure from energy-minimized complex with design 1 [2] Crystallographic ligand (MAT-POS-b3e365b9-1) [3] Binding modes generated for S-enantiomers of MAT-POS-dd3ad2b5-4 and MAT-POS-dd3ad2b5-2 (both ligands appear to accept HB from Q189 side chain) [4] Binding modes generated for designs 1 and 2 (neither ligand appears to accept HB from Q189 side chain).