Submission Details
Molecule(s):
CC(=O)N[C@@H](Cc1c[nH]c2ncccc12)C(=O)NCC#CBr
CC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCC#CBr
COc1cccc2[nH]cc(C[C@H](NC(C)=O)C(=O)NCC#CBr)c12
CC(=O)N[C@@H](Cc1c[nH]c2ncccc12)C(=O)NCc1ccccc1
CC(=O)N[C@@H](Cc1c[nH]c2ncccc12)C(=O)NCc1ccc(Cl)cc1
CC(=O)N[C@@H](Cc1c[nH]c2ncccc12)C(=O)NCc1cccc(Cl)c1
CC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1
Design Rationale:
These compounds are analogues of x0967. What is desirable about this molecule is that it is able to occupy the only deep binding pocket (containing tyrosine54) with the bromoacetylene moiety and, at the same time, with its paraphenol moiety, occupy the binding pocket containing cysteine145 and histidine162. The side chain containing the acetamide appears to be making a H-bond also. An overlay of the PDB files of x0967, x1249 and x1093 bound onto the protein leads to these structures. The idea being to replace the phenol, which has the potential for glucuronidation, with an indole or pyrrolopyridine. The methoxy group on the indole in one analogue seeks to find an H-bond.