title: Targeting Different Transthyretin Binding Sites with Unusual Natural Compounds.
abstract: Misfolding and aggregation of the transthyretin (TTR) protein leads to certain forms of amyloidosis. Some nutraceuticals, such as flavonoids and natural polyphenols, have recently been investigated as modulators of the self-assembly process of TTR, but they generally suffer from limited bioavailability. To discover innovative and more bioavailable natural compounds able to inhibit TTR amyloid formation, a docking study was performed using the crystallographic structure of TTR. This computational strategy was projected as an ad hoc inspection of the possible relationship between binding site location and modulation of the assembly process; interactions with the as-yet-unexplored epigallocatechin gallate (EGCG) sites and with the thyroxine (T4) pocket were simultaneously analyzed. All the compounds studied seem to prefer the traditional T4 binding site, but some interesting results emerged from the screening of an in-house database, used for validating the computational protocol, and of the Herbal Ingredients Targets (HIT) catalogue available on the ZINC database.
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, V. Bonanno 6, 56126, Pisa, Italy. gabriella.ortore@unipi.it.
authors.forename: Gabriella
authors.identifier: 0000-0002-1541-6258
authors.initials: G
authors.lastname: Ortore
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, V. Bonanno 6, 56126, Pisa, Italy.
authors.forename: Elisabetta
authors.identifier: 0000-0003-3398-2787
authors.initials: E
authors.lastname: Orlandini
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, V. Bonanno 6, 56126, Pisa, Italy.
authors.forename: Alessandra
authors.identifier: 0000-0002-9838-0448
authors.initials: A
authors.lastname: Braca
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, V. Bonanno 6, 56126, Pisa, Italy.
authors.forename: Lidia
authors.identifier: 0000-0002-2762-1929
authors.initials: L
authors.lastname: Ciccone
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, V. Bonanno 6, 56126, Pisa, Italy.
authors.forename: Armando
authors.identifier: 0000-0002-6795-8091
authors.initials: A
authors.lastname: Rossello
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, V. Bonanno 6, 56126, Pisa, Italy.
authors.forename: Adriano
authors.identifier: 0000-0002-7197-0552
authors.initials: A
authors.lastname: Martinelli
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, V. Bonanno 6, 56126, Pisa, Italy. susanna.nencetti@unipi.it.
authors.forename: Susanna
authors.identifier: 0000-0002-3547-7277
authors.initials: S
authors.lastname: Nencetti
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D059808:Polyphenols / Q000737:chemistry / Q000494:pharmacology*; D011228:Prealbumin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001688:Biological Products; D005419:Flavonoids; D059808:Polyphenols; D011228:Prealbumin
keywords: docking; fibril formation; natural products; transthyretin; virtual screening