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 adhoc 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

Oxidized epigallocatechin gallate inhibited lysozyme fibrillation more strongly than the native form

“…Molecular dynamic simulations have also usually been utilized to provide an atomistic explanation of the interactions between an intact polyphenol and polypeptide chains in the amyloid inhibition [40], [41], [42]. The data presented herein suggest that the oxidation of a polyphenol should be considered adequately in its anti-amyloidogenic actions.…”

Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4′-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors

“…Herein, due to the novelty of the 4,4 -bipyridyl motif in this field, a blind docking [21] exploration was performed in order to inspect the disposition of all enantiomers (M) and (P) of compounds 1-5 and the achiral 6 into the whole TTR, focusing on the binding capability toward the T 4 pockets. Despite the fact that flexible docking is frequently used to model ligand-receptor complexes accounting for molecular flexibility [64,65], we do not consider protein flexibility herein, rather focusing on the capability of the new compounds to insert in the same T 4 binding cavity hosting T 4 , as derived from the selected crystal complex.…”

“…In the last decades, several small molecules have proven to be able to bridge neighbouring monomers of TTR via specific hydrophobic and electrostatic noncovalent interactions, to stabilize the tetramer, to inhibit the tetramer dissociation, and to reduce FF [3,[15][16][17][18][19][20][21][22][23][24][25][26][27][28]. However, to date few structures possess the requirements to be drug candidates (Figure 1b), and the ATTR still lacks an effective therapy.…”

Identification of Transthyretin Fibril Formation Inhibitors Using Structure‐Based Virtual Screening

“…These dispositions probably stabilize the tetramer either by inducing interactions between different monomers or functioning as bridges themselves, linking two monomers. Only one crystal structure of TTR, that complexed with epigallocatechin gallate, features three different binding sites, all novel and distinct from those of the traditional variety; this has been the object of a distinct computational study …”

“…Only one crystal structure of TTR, that complexed with epigallocatechin gallate, [5] features three different binding sites, all novel and distinct from those of the traditional variety;t his has been the object of ad istinct computational study. [12] Among TTR crystallographic structures, approximately 100 contain the protein in its wild-type (wt) form, and among Transthyretin (TTR) is the primary carrierf or thyroxine (T 4 )i n cerebrospinal fluid and as econdary carrier in blood. TTR is as table homotetramer,b ut certain factors, genetic or environmental, could promote its degradation to form amyloid fibrils.…”