Submission Details
Molecule(s):
O=C1CC(=O)CC([C@@H](NS(=O)(=O)c2cccs2)c2ccc(F)cc2)C1
O=C1CC(=O)CC([C@@H](NC(=O)c2cccs2)c2ccc(F)cc2)C1
O=C1C=CC[C@H]([C@@H](NC(=O)c2cccs2)c2ccc(F)cc2)N1
O=C1C=C[C@H]([C@@H](NC(=O)c2cccs2)c2ccc(F)cc2)CN1
O=C1C=CC[C@@H]([C@@H](NC(=O)c2cccs2)c2ccc(F)cc2)N1
O=C1CC(=O)N(c2ccc(-c3cc[nH]c3)[nH]2)[C@H](Oc2ccc(F)cc2)C1
O=C1C=CC[C@@H](Oc2ccc(F)cc2)N1c1ccc(-c2cc[nH]c2)[nH]1
Design Rationale:
These designs are based on a number of mergings of the non-warhead portions of X_0759, X_1336, and X_1412. The two sets of warheads were explored in this set - cyclic acrylamides, and a cyclic diketone nucleoplile. The rationale for this choice is to explore whether the nucleophilic thiolate cysteine species is the most abundant, or whether the oxidized electrophilic sulfenic acid species predominates. The non-covalently bound encounter complex of the 3 fragments listed were modeled based on the covalent complex structures. The MOE structure prep and protonate 3D tools were used to prepare the structures for docking. Worth noting that the cysteine is predicted to be deprotonated in the presence of a bound ligand, likely due to the abundance of positive charge in the local environment. Designs were prioritized based on those that didn't move the terminal functional groups (fluoro-phenyl, thiophene) relative to their positions in the non-covalent models from the crystal structures.