title: The anti-fibrillogenic activity of tetracyclines on PrP 106-126: a 3D-QSAR study.
abstract: There is evidence that Tetracyclines are potentially useful drugs to treat prion disease, the fatal neurodegenerative disease in which cellular prion proteins change in conformation to become a disease-specific species (PrP(Sc)). Based on an in vitro anti-fibrillogenesis test, and using the peptide PrP106-126 in the presence of tetracycline and 14 derivatives, we carried out a three-dimensional quantitative structure-activity relationship (3D-QSAR) study to investigate the stereoelectronic features required for anti-fibrillogenic activity. A preliminary variable reduction technique was used to search for grid points where statistical indexes of interaction potential distributions present local maximum (or minimum) values. Variable selection genetic algorithms were then used to search for the best 3D-QSAR models. A 6-variable model showed the best predictability of the anti-fibrillogenic activity that highlighted the best tetracycline substitution patterns: hydroxyl group presence in positions 5 and 6, electrodonor substituents on the aromatic D-ring, alkylamine substituent at the amidic group in position 2 and non-epi configuration of the NMe2 group.
authors.affiliation: Dipartimento di Scienze dell'Ambiente e del Territorio, Università degli Studi di Milano-Bicocca, Milan, Italy. ugo.cosentino@unimib.it
authors.forename: Ugo
authors.initials: U
authors.lastname: Cosentino
authors.forename: Demetrio
authors.initials: D
authors.lastname: Pitea
authors.forename: Giorgio
authors.initials: G
authors.lastname: Moro
authors.forename: Gloria A A
authors.initials: GA
authors.lastname: Saracino
authors.forename: Pietro
authors.initials: P
authors.lastname: Caria
authors.forename: Rosaria M
authors.initials: RM
authors.lastname: Varì
authors.forename: Laura
authors.initials: L
authors.lastname: Colombo
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
mesh_terms: D016874:Neurofibrillary Tangles / Q000187:drug effects*; D010446:Peptide Fragments / Q000187:drug effects*; D011328:Prions / Q000187:drug effects*; D021281:Quantitative Structure-Activity Relationship; D013754:Tetracyclines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D010446:Peptide Fragments; D011328:Prions; D013754:Tetracyclines; C082632:prion protein (106-126)