title: 1,2,4-Oxadiazoles identified by virtual screening and their non-covalent inhibition of the human 20S proteasome.
abstract: Although several constitutive proteasome inhibitors have been reported these recent years, potent organic, noncovalent and readily available inhibitors are still poorly documented. Here we used a structure- and ligand-based in silico approach to identify commercially available 1,2,4-oxadiazole derivatives as non-covalent human 20S proteasome inhibitors. Their optimization led to the newly synthesized compound 4h that is a mixed proteasomal inhibitor of the chymotrypsin- like activity (K(i) of 26,1 nM and K'(i) of 7.5 nM) which is in addition selective versus the challenging cathepsin B and calpain proteases. Molecular modelling studies corroborated the mechanism of inhibition and suggest an unusual binding of the inhibitor within the S5 binding pocket (β6 subunit). The cellular effects of our compounds validate their utility as potential pharmacological agents for anti-cancer pre-clinical studies.
authors.affiliation: Enzymologie Moléculaire et Fonctionnelle, UR4, UPMC-Sorbonne Universités, Case 256, 7 Quai Saint Bernard, F75252 Paris Cedex 05, France.
authors.forename: X
authors.initials: X
authors.lastname: Maréchal
authors.forename: E
authors.initials: E
authors.lastname: Genin
authors.forename: L
authors.initials: L
authors.lastname: Qin
authors.forename: O
authors.initials: O
authors.lastname: Sperandio
authors.forename: M
authors.initials: M
authors.lastname: Montes
authors.forename: N
authors.initials: N
authors.lastname: Basse
authors.forename: N
authors.initials: N
authors.lastname: Richy
authors.forename: M A
authors.initials: MA
authors.lastname: Miteva
authors.forename: M
authors.initials: M
authors.lastname: Reboud-Ravaux
authors.forename: J
authors.initials: J
authors.lastname: Vidal
authors.forename: B O
authors.initials: BO
authors.lastname: Villoutreix
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D062105:Molecular Docking Simulation; D010069:Oxadiazoles / Q000737:chemistry* / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D010069:Oxadiazoles; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex