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 (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.
Vicik
Radim
R
Institute of Pharmacy and Food Chemistry, Department of Pharmaceutical/Medicinal Chemistry, University of Würzburg, Am Hubland, Würzburg, Germany.
Busemann
Matthias
M
Gelhaus
Christoph
C
Stiefl
Nikolaus
N
Scheiber
Josef
J
Schmitz
Werner
W
Schulz
Franziska
F
Mladenovic
Milena
M
Engels
Bernd
B
Leippe
Matthias
M
Baumann
Knut
K
Schirmeister
Tanja
T
D000818:Animals; D001388:Aziridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D016805:Paramecium tetraurelia / Q000201:enzymology; D011789:Quantum Theory; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001388:Aziridines; D015853:Cysteine Proteinase Inhibitors; D008024:Ligands; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L