Scrutiny of the mechanism of small molecule inhibitor preventing conformational transition of amyloid-β₄₂ monomer: insights from molecular dynamics simulations

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by loss of intellectual functioning of brain and memory loss. According to amyloid cascade hypothesis, aggregation of amyloid-β (Aβ) peptide can generate toxic oligomers and their accumulation in the brain is responsible for the onset of AD. In spite of carrying out a large number of experimental studies on inhibition of Aβ aggregation by small molecules, the detailed inhibitory mechanism remains elusive. In the present study, comparable molecular dynamics (MD) simulations were performed to elucidate the inhibitory mechanism of a sulfonamide inhibitor C1 (2,5-dichloro-N-(4-piperidinophenyl)-3-thiophenesulfonamide), reported for its in vitro and in vivo anti-aggregation activity against Aβ. MD simulations reveal that C1 stabilizes native α-helix conformation of Aβ by interacting with key residues in the central helix region (13-26) with hydrogen bonds and π-π interactions. C1 lowers the solvent-accessible surface area of the central hydrophobic core (CHC), KLVFF (16-20), that confirms burial of hydrophobic residues leading to the dominance of helical conformation in the CHC region. The binding free energy analysis with MM-PBSA demonstrates that Ala2, Phe4, Tyr10, Gln15, Lys16, Leu17, Val18, Phe19, Phe20, Glu22, and Met35 contribute maximum to binding free energy (-43.1 kcal/mol) between C1 and Aβ monomer. Overall, MD simulations reveal that C1 inhibits Aβ aggregation by stabilizing native helical conformation and inhibiting the formation of aggregation-prone β-sheet conformation. The present results will shed light on the underlying inhibitory mechanism of small molecules that show potential in vitro anti-aggregation activity against Aβ.

Benzofuran and Indole: Promising Scaffolds for Drug Development in Alzheimer's Disease

“…In this regard, studies of protein aggregation by using computer simulations have providedk ey insight into the molecular mechanism of AD and can be employed to design more potent novel inhibitors. [154] Another major challenge is the lack of efficient biomarkers that can detectt he disease at an early stage. Much earlier detection of the disease could be possible by the use of neuroimaging and biomarkers in the cerebrospinal fluid or plasma.F urthermore,t he drug candidate is required to cross the blood-brain barriera nd that too in a therapeutically appropriate concentration.…”

Molecular Dynamics Simulation of Collagen Binding to an Amyloid-Beta Monomer and its Effect on the Peptide Structure

“…MD simulations were performed using the GROMACS 5.1.4 package [16] with the GROMOS96 43A1 force field [17], which has been widely used for the conformational change analysis of Aβ [18][19][20][21][22][23][24]. The Aβ42 and the docked complex of Aβ42-1BKV obtained from the HDOCK server were selected for MD simulations and the two systems were named Aβ42-APO and Aβ42-1BKV complex, respectively.…”

Combined Modeling Study of the Binding Characteristics of Natural Compounds, Derived from Psoralea Fruits, to β-Amyloid Peptide Monomer

“…Definitely, Phe residues initiate the hydrophobic clustering of amyloid proteins and is considered central in the Aβ fibrillation process [ 12 ]. Shuaib and Goyal observed that a sulfonamide molecule stabilizes native α-helix conformation over the β-sheet form using 200 ns MD simulation [ 13 ]. Moreover, from molecular dynamic (MD) simulations it was reported that flavonoid compounds (E)-5-(4-hydroxystyryl)quinolone-8-ol, J147 derivative, and edaravone prevent the amyloid-Aβ42 conformational transition by disrupting its Asp23–Lys28 salt bridge [ 14 , 15 ].…”