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Aziridide‐Based Inhibitors of Cathepsin L: Synthesis, Inhibition Activity, and Docking Studies
Author(s) -
Vicik Radim,
Busemann Matthias,
Gelhaus Christoph,
Stiefl Nikolaus,
Scheiber Josef,
Schmitz Werner,
Schulz Franziska,
Mladenovic Milena,
Engels Bernd,
Leippe Matthias,
Baumann Knut,
Schirmeister Tanja
Publication year - 2006
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200600106
Subject(s) - aziridine , docking (animal) , stereochemistry , chemistry , active site , cathepsin , amino acid , serine , enzyme inhibitor , cathepsin b , cysteine , biochemistry , enzyme , ring (chemistry) , organic chemistry , medicine , nursing
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 n M ) (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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