title: Aziridide-based inhibitors of cathepsin L: synthesis, inhibition activity, and docking studies.
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.
authors.affiliation: Institute of Pharmacy and Food Chemistry, Department of Pharmaceutical/Medicinal Chemistry, University of Würzburg, Am Hubland, Würzburg, Germany.
authors.forename: Radim
authors.initials: R
authors.lastname: Vicik
authors.forename: Matthias
authors.initials: M
authors.lastname: Busemann
authors.forename: Christoph
authors.initials: C
authors.lastname: Gelhaus
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Stiefl
authors.forename: Josef
authors.initials: J
authors.lastname: Scheiber
authors.forename: Werner
authors.initials: W
authors.lastname: Schmitz
authors.forename: Franziska
authors.initials: F
authors.lastname: Schulz
authors.forename: Milena
authors.initials: M
authors.lastname: Mladenovic
authors.forename: Bernd
authors.initials: B
authors.lastname: Engels
authors.forename: Matthias
authors.initials: M
authors.lastname: Leippe
authors.forename: Knut
authors.initials: K
authors.lastname: Baumann
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
mesh_terms: 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
chemical_list: D001388:Aziridines; D015853:Cysteine Proteinase Inhibitors; D008024:Ligands; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L