Submission Details
Molecule(s):
CO[C@@]1(C(=O)Nc2cncc3ccccc23)CN(S(=O)(=O)N(C)C)Cc2ccc(Cl)cc21
Design Rationale:
Locking the configuration of the chiral center of X-SO2-substituted tetrahydroisquinolines such as MAT-POS-dd3ad2b5-4 (racemic; X=Me; pIC50 = 6.7) or MAT-POS-4223bc15-2 (racemic; X=NMe2; pIC50 = 6.9) with methoxy is likely to invert the direction of the S-X vector. This means that it cannot be assumed that SAR developed for des-methoxy analogs will necessarily transfer to methoxy analogs. The single design in this submission is intended to help map the SAR for X-SO2 substituted tetrahydroisoquinolines in which the configuration of the chiral center has been locked with methoxy.
Other Notes:
Protein-ligand complexes (P0157 A chain) were energy-minimized using Szybki (MMFF94S; amide carbonyl O and isoquinoline N fixed at the positions of the crystallographic ligand). The PDB file associated with this submission contains the following: [1] P0157 A chain from energy-mimimized complex with Design 1 [2] P0157 A chain crystallographic ligand (PET-UNK-29afea89-2) [3] Binding mode predicted for Design 1.