Submission Details
Molecule(s):
C[C@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC1CCNCC1)C(=O)N[C@H](C=O)C[C@@H]1CCNC1=O
Design Rationale:
Goal: Design an irreversible, peptidomimetic cysteine protease inhibitor. Strategy: Optimize potency from structurally-enabled inhibitor, TG-0205221. TG-0205221 (has a cyclohexyl instead of the proposed ideas with a piperidine) data shows: SARS CLpro Ki 53 nM, and SARS Vero-E6 Cell EC50 600 nM. From the crystal structure (PDB:2GX4), the inhibitor binds in the cleft between Protomer B and C of the dimer (binds in each asymmetric unit). From the crystal structure, most (5 of 6) of the hydrogen bonds are with Protomer C. The idea is to boost potency by substituting the cyclohexyl moiety for a basic amine (piperdine). The cyclohexyl seems to snake down the S2 pocket in Protomer B where the terminus is a Tyrosine residue (Tyr54). Based off of the model of the piperdine compared to the crystal structure of TG-0205221, the basic amine could sit over the tyrosine and form a hydrogen bond to boost potency. From heavy atom to heavy atom they are 2.8 angstrom away. Not the ideal length for a hydrogen bond but could potentially give you some boost in activity. This could be an efficient substitution that doesn't require larger decorations to the molecule and gives a quick go/no-go on this hypothesis. Although this molecule has a number of structure alerts, its structure is similar to molecules that at least made it into Phase 1 clinical trials.