Submission Details
Molecule(s):
Cc1cccc(CO)c1NC(=O)NC(Cc1ccc(O)cc1)C(=O)N(CCCC(N)=O)CCNC(CS)C(=O)O
Cc1cccc(CO)c1NC(=O)NC(Cc1ccc(O)cc1)C(=O)N(CCCC(N)=O)CCN1CCCN(C(=O)CCl)C1
Design Rationale:
Fragment 967 is potentially very useful as it has very good 3D-shape complementarity, and the phenol has induced a sidechain flip in N142 creating a parallel surface and nicely burying the phenol aromatic group. Phenol oxygen pincered between His163 and main-chain oxygen of Phe140 with 2 H-bonds. Fragment 967 is also well positioned for extension into the cleft between Pro168 and E189, which region is largely unexploited in the initial fragment set. Terminal carbon in this direction ~3.3A from main-chain oxygen of E166, potential enhancement by shift from amide to ureido with further extension into the P168/E189 cleft. I previously designed some non-covalent molecules based on the above with either a benzyl or butyramide group replacing the bromopropyne group of fragment 967. These ligands mostly project away from the covalent cysteine attachment point so could possibly be converted to covalents by attaching a suitable warhead I have subsequently downloaded SeeSAR and checked through my ligands finding one predicted to retain nanomolar affinity when trimmed back to a free N pointing toward the active cysteine. The above structures have a couple of possible warheads attached to this.
Other Notes:
I have uploaded the 'trimmed' parental compound which has nanomolar SeeSAR predicted potency. I'm not a chemist / have limited experience of covalent screening so if anyone can download this model and see better warheads that would enhance affinity then that would be great.....