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Aziridide-based inhibitors of cathepsin L: synthesis, inhibition activity, and docking studies
Radim Vicik1, Matthias Busemann, Christoph Gelhaus
1Institute of Pharmacy and Food Chemistry, Department of Pharmaceutical/Medicinal Chemistry, University of Würzburg, Am Hubland, Würzburg, Germany.
Abstract:
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 (K(i)=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.
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