Submission Details
Molecule(s):
PET-UNK-158bee2a-1
Duplicate of:
VLA-UNK-4cf5aa07-1
O=C(Cc1cccc(Cl)c1)Nc1snc2ccccc12
O=C(Cc1cccc(Cl)c1)Nc1ccns1
Cc1cnsc1NC(=O)Cc1cccc(Cl)c1
O=C(Cc1cccc(Cl)c1)Nc1ncns1
O=C(Nc1snc2ccccc12)[C@@H]1CCOc2ccc(Cl)cc21
O=C(Nc1ccns1)[C@@H]1CCCc2ccc(Cl)cc21
Cc1cnsc1NC(=O)[C@@H]1CCOc2ccc(Cl)cc21
O=C(Nc1ncns1)[C@@H]1CCCc2ccc(Cl)cc21
O=C(Nc1snc2ccccc12)[C@@H]1CCS(=O)(=O)c2ccc(Cl)cc21
O=C(Nc1ccns1)[C@@H]1CCS(=O)(=O)c2ccc(Cl)cc21
Cc1cnsc1NC(=O)[C@@H]1CCS(=O)(=O)c2ccc(Cl)cc21
O=C(Nc1ncns1)[C@@H]1CCS(=O)(=O)c2ccc(Cl)cc21
CS(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2snc3ccccc23)C1
CS(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2ccns2)C1
Cc1cnsc1NC(=O)[C@@H]1CN(S(C)(=O)=O)Cc2ccc(Cl)cc21
CS(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2ncns2)C1
Design Rationale:
This is a speculative submission and is based on the hypothesis that a sulfur atom next to the nitrogen that accepts a hydrogen bond from the protein may be able to interact with thiol of the catalytic cysteine. Interactions like the one hypothesized are similar to ‘halogen bonds’ and are referred to as ‘chalcogen bonds’. This submission uses 4 P1 heterocycles which have been linked to 4 different P2 substituents to give a total of 16 designs. Benzoisothiazole, isothiazole and methylisothiazole have been included for their potential to serve as chalcogen bond donors while 1,2-4-thiadiazole may be able to form a covalent bond with the catalytic cysteine. It should be possible to test the hypothesis behind this submission with Designs 1-4 (3-chlorobenzyl at P2) although I have included other P2 substituents to provide the design team with additional options.
Other Notes:
Design 1 is a re-submission of VLA-UNK-4cf5aa07-1 and this is indicated in the PDB file associated with this submission. Protein-ligand complexes (X11612 A chain) were energy minimized using Szybki (MMFF94S; no constraint of atoms in ligand structure). The PDB file associated with this submission contains the following: [1] X11612 A chain [2] X11612 A chain crystallographic ligand (MAT-POS-b3e365b9-1) [3-18] Designs 1-16.