Combined in silico approaches for the identification of novel inhibitors of human islet amyloid polypeptide (hIAPP) fibrillation

• Published in: Journal of molecular graphics & modelling Vol. 77; pp. 295 - 310
• Main Authors: Patel, Palak, Parmar, Krupali, Vyas, Vivek K., Patel, Dhaval, Das, Mili
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2017
• Subjects: Amino Acid Sequence; Amyloid - antagonists & inhibitors; Amyloid - chemistry; Binding free energy; Computational docking; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Glucose - chemistry; Glucose - metabolism; Humans; Insulin - chemistry; Islet amyloid polypeptide; Islet Amyloid Polypeptide - antagonists & inhibitors; Islet Amyloid Polypeptide - chemistry; Molecular Dynamics Simulation; Pharmacophore modeling; Protein Aggregation, Pathological - metabolism; Protein Conformation; Protein structure prediction; Pharmacophore modeling; Computational docking; Protein structure prediction; Binding free energy; Molecular dynamics simulation; Islet amyloid polypeptide
• ISSN: 1093-3263; 1873-4243
• DOI: 10.1016/j.jmgm.2017.09.004

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•Small molecules interact with helices and prevent hIAPP from adopting β-sheet structure.•Residue Phenylalanine 23 should play an important role in inhibiting hIAPP fibrillation.•Effective binding of small molecules with neighboring β-strands should lead to stabilization of fibrils.•Mixture of small molecules targeting fibrils from diverse polypeptides should be required for treatment of aggregation diseases.
Human islet amyloid polypeptide (hIAPP) is a natively unfolded polypeptide hormone of glucose metabolism, which is co-secreted with insulin by the β-cells of the pancreas. In patients with type 2 diabetes, IAPP forms amyloid fibrils because of diabetes-associated β-cells dysfunction and increasing fibrillation, in turn, lead to failure of secretory function of β-cells. This provides a target for the discovery of small organic molecules against protein aggregation diseases. However, the binding mechanism of these molecules with monomers, oligomers and fibrils to inhibit fibrillation is still an open question. In this work, ligand and structure-based in silico approaches were used to identify novel fibrillation inhibitors and/or fibril binding compounds. The best pharmacophore model was used as a 3D search query for virtual screening of a compound database to identify novel molecules having the potential to be therapeutic agents against protein aggregation diseases. Docking and molecular dynamics simulation studies were used to explore the interaction pattern and mechanism of the identified novel small molecules with predicted hIAPP structure, its aggregation prone conformation and fibril forming segments. We show that catechins with galloyl group and molecules having two to three planar apolar rings bind to hIAPP structures and fibril forming segments with greater affinity. The differences in binding affinities of different compounds against several fibril forming segments of the peptide suggest that a mixture of active compounds may be required for treatment of aggregation diseases.