Withanolide A inhibits hIAPP aggregation: An In silico, biophysical, and drosophila-based In vivo validation

Area of Science:

• Biochemistry
• Pharmacology
• Molecular Biology

Background:

• Aberrant aggregation of human islet amyloid polypeptide (hIAPP) causes pancreatic β-cell dysfunction and death, a hallmark of Type II diabetes mellitus (T2DM).
• Identifying inhibitors of hIAPP aggregation is crucial for developing T2DM therapeutics.

Purpose of the Study:

• To identify natural product inhibitors of hIAPP aggregation using computational and experimental methods.
• To evaluate the therapeutic potential of Withanolide A in preclinical models of T2DM.

Main Methods:

• Virtual screening of 2000 phytoconstituents using molecular docking and ADMET predictions.
• Molecular dynamics (MD) simulations to analyze hIAPP-ligand interactions and fibril formation.
• Experimental validation using Thioflavin T assays, FTIR, Confocal, and Transmission Electron Microscopy (TEM).
• In vivo studies in Drosophila models to assess Withanolide A's efficacy against hIAPP toxicity and hyperglycemia.

Main Results:

• Withaferin A and Withanolide A were identified as lead compounds with favorable drug-like properties.
• Withanolide A demonstrated potent inhibition of hIAPP aggregation by increasing lag phase, reducing β-sheet content, and preventing fibril formation.
• In vivo, Withanolide A mitigated hIAPP oligomer-induced toxicity, reduced oxidative stress, and lowered glucose levels in diabetic Drosophila.

Conclusions:

• Withanolide A effectively inhibits hIAPP aggregation and exhibits anti-diabetic activity.
• Withanolide A shows promise as a potential therapeutic candidate for T2DM by targeting hIAPP aggregation.