title: 5-Benzylidene-hydantoin is a new scaffold for SIRT inhibition: From virtual screening to activity assays.
abstract: Sirtuins (SIRTs) are a family of enzymes able to catalyze the deacetylation of the N-acetyl lysines of both histone and non-histone substrates. Inhibition of SIRTs catalytic activity was recently reported in the literature as being beneficial in human diseases, with very promising applications in cancer therapy and enzymatic neurodegeneration. By combining a structure-based virtual screening of the Specs database with cell-based assays, we identified the 5-benzylidene-hydantoin as new scaffold for the inhibition of SIRT2 catalytic activity. Compound 97 (Specs ID AH-487/41657829), active in the low μM range against SIRT2, showed the optimal physicochemical properties for passive absorption as well as relatively low cytotoxicity in vitro. Further studies revealed non-competitive and mixed-type kinetics toward acetyl-lysine substrates and NAD(+), respectively, and a non-selective profile for SIRT inhibition. A binding mode consistent with the experimental evidence was proposed by molecular modeling. Additionally, the levels of acetyl-p53 were shown to be increased in HeLa cells treated with 97. Taken together, these results encourage further investigation of 5-benzylidene-hydantoin derivatives for their SIRT-related therapeutic effects.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva-University of Lausanne, 30 quai E. Ansermet, CH-1211 Geneva 4, Switzerland.
authors.forename: Lionel
authors.initials: L
authors.lastname: Sacconnay
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva-University of Lausanne, 30 quai E. Ansermet, CH-1211 Geneva 4, Switzerland.
authors.forename: Lucie
authors.initials: L
authors.lastname: Ryckewaert
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva-University of Lausanne, 30 quai E. Ansermet, CH-1211 Geneva 4, Switzerland.
authors.forename: Giuseppe Marco
authors.initials: GM
authors.lastname: Randazzo
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva-University of Lausanne, 30 quai E. Ansermet, CH-1211 Geneva 4, Switzerland.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Petit
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva-University of Lausanne, 30 quai E. Ansermet, CH-1211 Geneva 4, Switzerland.
authors.forename: Carolina Dos Santos
authors.initials: Cdos S
authors.lastname: Passos
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, LT-02241 Vilnius, Lithuania.
authors.forename: Jelena
authors.initials: J
authors.lastname: Jachno
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, LT-02241 Vilnius, Lithuania.
authors.forename: Vilma
authors.initials: V
authors.lastname: Michailovienė
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, LT-02241 Vilnius, Lithuania.
authors.forename: Asta
authors.initials: A
authors.lastname: Zubrienė
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, LT-02241 Vilnius, Lithuania.
authors.forename: Daumantas
authors.initials: D
authors.lastname: Matulis
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva-University of Lausanne, 30 quai E. Ansermet, CH-1211 Geneva 4, Switzerland.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Carrupt
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva-University of Lausanne, 30 quai E. Ansermet, CH-1211 Geneva 4, Switzerland. Electronic address: claudia.avello@unige.ch.
authors.forename: Claudia Avello
authors.initials: CA
authors.lastname: Simões-Pires
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva-University of Lausanne, 30 quai E. Ansermet, CH-1211 Geneva 4, Switzerland. Electronic address: alessandra.nurisso@unige.ch.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Nurisso
mesh_terms: D000107:Acetylation / Q000187:drug effects; D001597:Benzylidene Compounds / Q000737:chemistry* / Q000494:pharmacology*; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006827:Hydantoins / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D008239:Lysine / Q000378:metabolism; D037761:Sirtuins / Q000037:antagonists & inhibitors*
chemical_list: D001597:Benzylidene Compounds; D056572:Histone Deacetylase Inhibitors; D006827:Hydantoins; D037761:Sirtuins; D008239:Lysine
keywords: 5-Benzylidene-hydantoin; Enzymology; Molecular dynamics; PAMPA; Sirtuins; Virtual screening; p53 acetylation