Submission Details

Design Rationale:

Rationale (Second round): Previously, a non-covalent ligand was designed targeting the termini regions of Mpro (https://covid.postera.ai/covid/submissions/066c4001-b6a3-47b7-83a4-5e7933997959), which are important for dimerization and protease activity. We then identified a reactive cysteine (Cys300) in a nearby pocket by using the ICM (MolSoft LLC) cysteine reactivity predictor. This proposal consists on designing compounds that mimic interactions of fragments x1086 and x1187 and are able to form a covalent bond with Cys300. Methodology: The previously identified non-covalent binder of Mpro was modified by introducing a reactive nitrile group in its side chain. Then, this compound was docked to Mpro using the CovDock tool in Schrodinger, and selecting Cys300 as the reactive residue. Although most docking poses had an exposed sulfonamide group, we identified a conformation that was able to mimic interactions observed in the crystal structure of Mpro bound to x1086, i.e. a p-p interaction with Phe8 and hydrogen bond interactions with the backbone of Met6. The non-aromatic 5-membered ring of our previously designed compound was not making favorable interactions with its surrounding residues, and therefore it was removed. Addition of a morpholine group was done aiming at occupying a similar site as observed in the crystal structure of x1187. A further addition of a cyclopropane (or methyl groups) was aimed at improving PK properties, as previously observed for other cysteine protease inhibitors(1). 1. https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0003916

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