title: Identification by in silico and in vitro screenings of small organic molecules acting as reversible inhibitors of kallikreins.
abstract: Netherton syndrome is caused by loss-of-function mutations in SPINK5 encoding the Kazal-type inhibitor LEKTI-1 leading to dysregulation of proteolytic cascades involving several kallikreins. We used both structure-based and ligand-based virtual screening computations to identify commercially available non-covalent inhibitors of human kallikrein 5 (hK5), a serine protease (trypsin-like) that plays a central role in the initiation of the molecular cascades leading to the Netherton syndrome phenotype. The efficacy and mechanism of inhibition of the identified new families of organic compounds were analyzed not only for hK5 but also on other proteases implicated in the cascades (hK7, hK14 and matriptase). These inhibitors are nontoxic on healthy human keratinocytes and are structurally different from traditional serine protease inhibitors validating their potential utility as initial hits to control proteolytic disorders observed in dermatological pathologies such as Netherton syndrome.
authors.affiliation: Enzymologie Moléculaire et Fonctionnelle, UR4, Université Pierre et Marie Curie - Sorbonne Universités (UPMC), case courrier 256, 7, quai St Bernard, 75252 Paris Cedex 05, France.
authors.forename: Xiao
authors.initials: X
authors.lastname: Tan
authors.forename: Claudia
authors.initials: C
authors.lastname: Bertonati
authors.forename: Lixian
authors.initials: L
authors.lastname: Qin
authors.forename: Laetitia
authors.initials: L
authors.lastname: Furio
authors.forename: Chahrazade
authors.initials: C
authors.lastname: El Amri
authors.forename: Alain
authors.initials: A
authors.lastname: Hovnanian
authors.forename: Michèle
authors.initials: M
authors.lastname: Reboud-Ravaux
authors.forename: Bruno O
authors.initials: BO
authors.lastname: Villoutreix
mesh_terms: D004305:Dose-Response Relationship, Drug; D057166:High-Throughput Screening Assays; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D015842:Serine Proteinase Inhibitors; D054852:Small Molecule Libraries; D007610:Kallikreins
keywords: 3-amino-7-methyl-coumarin; AMC; DMSO; In vitro screening; Kallikreins; LBVLS; LEKTI; Netherton syndrome; Reversible inhibitors; SBVLS; Skin diseases; Small organic molecules; Virtual screening; dimethylsulfoxide; hK; human kallikrein; ligand-based virtual ligand screening; lympho-epithelial Kazal-type inhibitor; structure-based virtual ligand screening