Submission Details
Molecule(s):
O=CN(C(=O)Cc1cccc(Cl)c1)c1cncc2ccccc12
COC(=O)N(C(=O)Cc1cccc(Cl)c1)c1cncc2ccccc12
Design Rationale:
Each of these two designs attaches a carbonyl-based warhead directly to the amide nitrogen of ADA-UCB-6c2cb422-1. As such, the designs are analogous to PET-UNK-5ecb6237-1 and NIR-WEI-75ed5c39-1. It is intended that the carbonyl oxygen of each warhead should function as a hydrogen bond acceptor in a similar manner to the amide carbonyl oxygen of the quinolone EDJ-MED-6af13d92-3. This would be expected to make the warheads more electrophilic when bound to target. I would anticipate that the first design (N-formyl) has the better chance of adopting the desired conformation. Covalent bond formation with warheads may lead to the designs functioning as substrates (benefits may result from slow dissociation of products).
Other Notes:
I am assuming that each design can be synthesized directly from ADA-UCB-6c2cb422-1. The pdb file associated with the submission contains the following: (1) X10959 protein (2) X10959 ligand ADA-UCB-6c2cb422-1 (3) EDJ-MED-6af13d92-3 (4) first design (with formyl warhead) (5) second design (with methoxycarbonyl warhead).