Molecular Dynamics Simulations Indicate Aromaticity as a Key Factor in the Inhibition of IAPP(20-29) Aggregation.
ACS Chem Neurosci
; 13(11): 1615-1626, 2022 06 01.
Article
em En
| MEDLINE
| ID: mdl-35587203
ABSTRACT
Islet amyloid polypeptide (IAPP) is a 37-residue amyloidogenic hormone implicated in the progression of Type II Diabetes (T2D). T2D affects an estimated 422 million people yearly and is a comorbidity with numerous diseases. IAPP forms toxic oligomers and amyloid fibrils that reduce pancreatic ß-cell mass and exacerbate the T2D disease state. Toxic oligomer formation is attributed, in part, to the formation of interpeptide ß-strands comprised of residues 20-29 (IAPP(20-29)). Flavonoids, a class of polyphenolic natural products, have been found experimentally to inhibit IAPP aggregate formation. Many of these small flavonoids differ structurally only slightly; the influence of functional group placement on inhibiting the aggregation of the IAPP(20-29) has yet to be explored. To probe the role of small-molecule structural features that impede IAPP aggregation, molecular dynamics simulations were performed to observe trimer formation on a model fragment of IAPP(20-29) in the presence of morin, quercetin, dihydroquercetin, epicatechin, and myricetin. Contacts between Phe23 residues were critical to oligomer formation, and small-molecule contacts with Phe23 were a key predictor of ß-strand reduction. Structural properties influencing the ability of compounds to disrupt Phe23-Phe23 contacts included aromaticity and carbonyl and hydroxyl group placement. This work provides key information on design considerations for T2D therapeutics that target IAPP aggregation.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
/
Polipeptídeo Amiloide das Ilhotas Pancreáticas
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
ACS Chem Neurosci
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos