Aziridide-Based Inhibitors of Cathepsin L: Synthesis, Inhibition Activity, and Docking Studies

A comprehensive screening of N‐acylated aziridine (aziridide) based cysteine protease inhibitors containing either Boc‐Leu‐Caa (Caa=cyclic amino acid), Boc‐Gly‐Caa, or Boc‐Phe‐Ala attached to the aziridine nitrogen atom revealed Boc‐(S)‐Leu‐(S)‐Azy‐(S,S)‐Azi(OBn)2 (18 a) as a highly potent cathepsin L (CL) inhibitor (Ki=13 nM) (Azy=aziridine‐2‐carboxylate, Azi=aziridine‐2,3‐dicarboxylate). Docking studies, which also accounted for the unusual bonding situations (the flexibility and hybridization of the aziridides) predict that the inhibitor adopts a Y shape and spans across the entire active site cleft, binding into both the nonprimed and primed sites of CL. Docking studies that accounted for the unusual bonding situation in a series of N‐acylated aziridines revealed that the most potent cathepsin L inhibitor (shown) adopts a Y‐shaped conformation. This binding mode results in the inhibitor spanning across the entire active site cleft of cathepsin L.