Submission Details




3-aminopyridine-like Ordered Check Availability on Manifold View



3-aminopyridine-like Check Availability on Manifold View

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 ( ) 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).

Inspired By:
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