Submission Details
Molecule(s):
O=C1C[C@]2(CN(Cc3nncs3)Cc3ccc(Cl)cc32)C(=O)N1c1cncc2ccccc12
O=C1c2ccc(Cl)cc2[C@@]2(CC(=O)N(c3cncc4ccccc34)C2=O)CN1Cc1nnco1
COC(=O)CN1C[C@]2(CC(=O)N(c3cncc4ccccc34)C2=O)c2cc(Cl)ccc2C1=O
O=C1CC2(CN(Cc3nncs3)Cc3ccc(Cl)cc32)C(=O)N1c1cncc2ccccc12
O=C1c2ccc(Cl)cc2C2(CC(=O)N(c3cncc4ccccc34)C2=O)CN1Cc1nnco1
COC(=O)CN1CC2(CC(=O)N(c3cncc4ccccc34)C2=O)c2cc(Cl)ccc2C1=O
Design Rationale:
MAT-POS-1bed62cf-3 and EDJ-MED-8bb691af-8 and the pendant amides of these have been replaced with 1,3,4-thiadazole (S mimics amide NH by interacting with neutral N of THIQ) and 1,3,4-oxadiazole (no need to mimic amide NH for DHIQ; thiadiazole is more lipophilic than oxadiazole and can potentially make undesirable interaction with DHIQ carbonyl oxygen). I have also replaced the pendant amide of EDJ-MED-8bb691af-8 with the methyl ester as Design 3 (this is likely to be synthetically more accessible than Design 2 and could be helpful in deciding whether to synthesize Design 2). The racemates for the designs have been included in this submission.
Other Notes:
Protein-ligand complexes (P1788 A chain) were energy-minimized using Szybki (MMFF94S). The PDB file associated with this submission contains the following: [1] P1788 A chain protein structure [2] P1788 A chain crystallographic ligand (MAT-POS-dc2604c4-1) [3-5] Binding modes predicted for Designs 1-3