Submission Details
Molecule(s):
O=C(Nc1cncc2ccccc12)[C@@H]1CN(Cc2ncon2)C(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2ccccc12)[C@@H]1CN(Cc2ncno2)C(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2ccccc12)C1CN(Cc2ncon2)C(=O)c2ccc(Cl)cc21
O=C(Nc1cncc2ccccc12)C1CN(Cc2ncno2)C(=O)c2ccc(Cl)cc21
Design Rationale:
The two designs in this submission are isomers (1,2,4-oxadiazoles) of the 1,3,4-oxadiazole PET-UNK-37251634-3 and each design has also been submitted as a racemate. 1,2,4-Oxadiazoles are expected to be more lipophilic (see https://doi.org/10.1021/jm2013248 ) than their 1,3,4-oxadiazole isomers and this reflects differences in the hydrogen bond basicity (see https://doi.org/10.1021/acs.jmedchem.5b01946 ). My recommendation would be to first synthesize the ester PET-UNK-c7ac4d9e-1 (it should be as accessible as the amide EDJ-MED-015fb6b4-2) before making a decision which (if any) synthesize oxadiazoles should be synthesized.
Other Notes:
Protein-ligand complexes (P1090 A chain) were energy-minimized using Szybki (MMFF94S) fixing the coordinates of the amide nitrogen and oxygen. The PDB file associated with this submission contains the following: [1] P0601 protein structure [2] P1090 A chain crystallographic ligand (MAT-POS-4223bc15-23) [3-4] Binding modes predicted for Designs 1 -2.