Unraveling the Interaction of a Neurological Drug Rivastigmine with Human Insulin Protein: A Biophysical Method in Combination with Molecular Docking and Molecular Dynamics Simulation

Abstract

The study aims to examine the aggregation of proteins due to their association with various conformational problems including well-known neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. In this context, we have studied the mechanistic route of the neurological drug rivastigmine on human insulin (HI) protein aggregation. The Thioflavin T and light scattering studies establish that the drug has the ability to inhibit HI fibrillation. It is pertinent to note here that rivastigmine has been anticipated to cross the blood–brain barrier. The dye 8-anilino-1-naphthalenesulfonic acid binding assays exhibit that the drug interferes with the hydrophobic domain of the protein because of intermolecular interaction. Furthermore, molecular docking and molecular dynamics simulation studies revealed the interactions of rivastigmine at the receptor site of acetylcholinesterase (AChE) and Aβ-42, thereby inhibiting the hydrolytic activity. Rivastigmine forms a hydrogen bond with the Tyr337 residue of AChE and His14 (chain C) and Gly33 (chain A) residues of Aβ-42, in addition to several weak interactions. The results showed the fundamental mechanisms of the inhibition of HI fibrillation by neurological drugs, which may provide ideas about the rational design of new lead therapeutics against amyloidosis.