Date: March 22, 2022
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 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 (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 were critical to oligomer formation, and small-molecule contacts with Phe23 were a key predictor of β-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. Additionally, this work provides a new framework for drug design using MD.
Kelsie King
Virginia Polytechnic Institute and State University
Molecular dynamics simulations exploring amyloid nucleation and aggregation cascades in complex microenvironments | Poster Board #9
Amyloid-β (Aβ) is an intrinsically disordered protein that is implicated in the progression of Alzheimer’s Disease…
Using MD simulations to explore the structural morphologies of cytotoxic and functional amyloids in microenvironments
Amyloids are a class of proteins marked by their tendency to aggregate into fibrils with a characteristic cross-β spine, yet they exist on a spectrum from functional, as in the case of the neuromodulator β-endorphin, to cytotoxic, as with amyloid-β…
Investigating the role of electronics and microenvironments on amyloid dynamics with MD simulations | Poster Board #836
Amyloids, defined as intrinsically disordered proteins, that polymerize into a cross-β structures, exhibit a unique propensity for modulating secondary and tertiary structures in response to environmental stimuli…
In silico discovery and design of drug leads for SARS-CoV-2 main protease (Mpro) using a hybrid evolutionary algorithm approach
Computer-aided drug design is instrumental in producing new lead compounds and compound classes to aid in the drug discovery pipeline. However, even with the advancements in computational virtual screening (VS) methods, discovery of a new drug is truly a challenging and time-consuming task…
