title: Biological and computational evaluation of resveratrol inhibitors against Alzheimer's disease.
abstract: It has been reported that beta amyloid induces production of radical oxygen species and oxidative stress in neuronal cells, which in turn upregulates β-secretase (BACE-1) expression and beta amyloid levels, thereby propagating oxidative stress and increasing neuronal injury. A series of resveratrol derivatives, known to be inhibitors of oxidative stress-induced neuronal cell death (oxytosis) were biologically evaluated against BACE-1 using homogeneous time-resolved fluorescence (TRF) assay. Correlation between oxytosis inhibitory and BACE-1 inhibitory activity of resveratrol derivatives was statistically significant, supporting the notion that BACE-1 may act as pivotal mediator of neuronal cell oxytosis. Four of the biologically evaluated resveratrol analogs demonstrated considerably higher activity than resveratrol in either assay. The discovery of some "hits" led us to initiate detailed docking studies associated with Molecular Dynamics in order to provide a plausible explanation for the experimental results and understand their molecular basis of action.
authors.affiliation: a Chemistry Department , University of Athens , Panepistimiopolis Zografou , Greece .
authors.forename: Catherine
authors.initials: C
authors.lastname: Koukoulitsa
authors.affiliation: b Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation , Athens , Greece .
authors.forename: Caroline
authors.initials: C
authors.lastname: Villalonga-Barber
authors.affiliation: b Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation , Athens , Greece .
authors.forename: Robert
authors.initials: R
authors.lastname: Csonka
authors.affiliation: b Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation , Athens , Greece .
authors.forename: Xanthippi
authors.initials: X
authors.lastname: Alexi
authors.affiliation: b Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation , Athens , Greece .
authors.forename: Georgios
authors.initials: G
authors.lastname: Leonis
authors.affiliation: c Institute of Accelerating Systems and Applications , Panepistimiopolis Zografou , Athens , Greece , and.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Dellis
authors.affiliation: d Medivir AB , Huddinge , Sweden.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hamelink
authors.affiliation: d Medivir AB , Huddinge , Sweden.
authors.forename: Oscar
authors.initials: O
authors.lastname: Belda
authors.affiliation: b Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation , Athens , Greece .
authors.forename: Barry R
authors.initials: BR
authors.lastname: Steele
authors.affiliation: b Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation , Athens , Greece .
authors.forename: Maria
authors.initials: M
authors.lastname: Micha-Screttas
authors.affiliation: b Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation , Athens , Greece .
authors.forename: Michael N
authors.initials: MN
authors.lastname: Alexis
authors.affiliation: b Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation , Athens , Greece .
authors.forename: Manthos G
authors.initials: MG
authors.lastname: Papadopoulos
authors.affiliation: a Chemistry Department , University of Athens , Panepistimiopolis Zografou , Greece .
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D051379:Mice; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D013267:Stilbenes; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D000077185:Resveratrol
keywords: Alzheimer’s disease; BACE-1; MM–PBSA; docking; free energy calculations; molecular dynamics; resveratrol analogs