Small Molecules as Amyloid Inhibitors: Molecular Dynamic Simulations with Human Islet Amyloid Polypeptide (IAPP)
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 co-morbidity with numerous diseases. IAPP forms toxic oligomers and amyloid fibrils that reduce pancreatic β-cell mass and exacerbate the T2D disease state. Toxic oligomer formation is attributed, in part, to the formation of inter-peptide β-strands comprised of residues 23-27 (FGAIL). Flavonoids, a class of polyphenolic natural products, have been found experimentally to inhibit IAPP aggregate formation. Many of these known IAPP aggregation attenuating 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 (MD) simulations were performed on a model fragment of IAPP(20-29) in the presence of morin, quercetin, dihydroquercetin, epicatechin, and myricetin. Contacts between Phe23 residues are critical to oligomer formation, and small-molecule contacts with Phe23 are a key predictor of β-strand reduction. Structural properties influencing the ability of compounds to disrupt Phe23-Phe23 contacts include carbonyl and hydroxyl group placement. These structural features influence aromaticity and hydrophobicity, principally affecting ability to disrupt IAPP(20-29) oligomer formation. This work provides key information on design considerations for T2D therapeutics.
General Audience Abstract
Type II Diabetes (T2D) affects an estimated 422 million people worldwide, with the World Health Organization (WHO) reporting that approximately 1.5 million deaths were directly caused by T2D in 2019. The progression of T2D has been attributed to a protein, called islet amyloid polypeptide (IAPP, or amylin) that is co-secreted with insulin after individuals eat or consumes calories. IAPP has been discovered to form toxic aggregates or clumps of protein material that worsen the disease state and cause a loss of mass of pancreatic cells. There is a large market for therapeutics of T2D and more small molecule drugs are needed to slow progression and severity of T2D. Flavonoids, a class of natural molecules, have been found to inhibit the processes by which IAPP promotes T2D disease progression by stopping the aggregation of IAPP. The structures of these flavonoid compounds differ slightly but show difference in ability to slow IAPP aggregation. By understanding how those differences confer more or less protection against T2D and inhibit IAPP aggregation, we can design more potent and specific drugs to target IAPP. To probe the role of molecular structure in preventing IAPP aggregation, molecular dynamics (MD) simulations — a powerful computational technique — were performed on a model fragment of IAPP in the presence of molecules morin, quercetin, dihydroquercetin, epicatechin, and myricetin. MD simulations provide extremely detailed information about potential drug interactions with a given target, serving as an important tool in the development of new drugs. This work has identified key features and predictors of effective IAPP drugs, providing a framework for the further development of therapeutics against T2D and similar diseases.
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