Submission Details
Molecule(s):
CC(=O)N[C@@H](Cc1ccc(O)c(F)c1)C(=O)NCC#CBr
CC(=O)N[C@@H](Cc1ccc(O)c(F)c1)C(=O)NCc1ccc(Cl)cc1
CC(=O)N[C@@H](Cc1ccc(O)c(F)c1)C(=O)NCc1cccc(Cl)c1
CC(=O)N[C@@H](Cc1ccc(O)c(F)c1)C(=O)NCC1CCN(C)CC1
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 x0981 bound onto the protein leads to these structures. x0967, x1249 and x0981 each have a substituent in the deep pocket and these analogues of x0967 seek to maximise the binding here. The addition of the fluoro group to the phenol could enhance the H-bonding effect of the OH and provide extra lipophilicity