Submission Details
Molecule(s):
CO[C@@]1(C(=O)Nc2cncc3ccccc23)CN(S(C)(=O)=O)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3ccc(F)cc23)CN(C(C)=O)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3ccccc23)CN(C(C)=O)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3ccc(F)cc23)CN(CC#N)Cc2ccc(Cl)cc21
CO[C@@]1(C(=O)Nc2cncc3ccccc23)CN(CC#N)Cc2ccc(Cl)cc21
Design Rationale:
The submission consists of 5 analogs of EDJ-MED-670ad2ee-3 in which the tetrahydroisoquinoline N is capped (methylsufonyl: design 1; acetyl: designs 2/3) or is rendered less basic (designs 4/5) by the cyanomethyl substituent (pKa of 5.3 has been reported for aminoacetonitrile in https://doi.org/10.1021/jo01098a603 )
Other Notes:
Hydrogen bond donation from the side chain NH of Q189 to the ligand is only likely for the N-acetyl analogs (designs 2/3). The A-chain of P0157 (ligand: PET-UNK-29afea89-2) was used to generate binding modes (MMFF94S using syzbki; isoquinoline 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 2 [2] Crystallographic ligand (PET-UNK-29afea89-2) [3] Proposed binding mode for EDJ-MED-670ad2ee-3 [4] Proposed binding modes for designs 1-5.