Aziridide‐Based Inhibitors of Cathepsin L: Synthesis, Inhibition Activity, and Docking Studies
2006; Wiley; Volume: 1; Issue: 10 Linguagem: Inglês
10.1002/cmdc.200600106
ISSN1860-7187
AutoresRadim Vičík, Matthias Busemann, Christoph Gelhaus, Nikolaus Stiefl, Josef Scheiber, Werner Schmitz, F. A. Schulz, Milena Mladenović, Bernd Engels, Matthias Leippe, Knut Baumann, Tanja Schirmeister,
Tópico(s)Organometallic Compounds Synthesis and Characterization
ResumoA 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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