Identification of new pentapeptides as potential inhibitors of amyloid-β₄₂ aggregation using virtual screening and...

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease mainly characterized by extracellular accumulation of amyloid-β (Aβ) peptide. Previous studies reported pentapeptide RIIGL as an effective inhibitor of Aβ aggregation and neurotoxicity induced by Aβ aggregates. In this work, a library of 912 pentapeptides based on RIIGL has been designed and assessed for their efficacy to inhibit Aβ₄₂ aggregation using computational techniques. The top hit pentapeptides revealed by molecular docking were further assessed for their binding affinity with Aβ₄₂ monomer using MM-PBSA (molecular mechanics Poisson-Boltzmann surface area) method. The MM-PBSA analysis identified RLAPV, RVVPI, and RIAPA, which bind to Aβ₄₂ monomer with a higher binding affinity -55.80, -46.32, and -44.26 kcal/mol, respectively, as compared to RIIGL (ΔG_binding = -41.29 kcal/mol). The residue-wise binding free energy predicted hydrophobic contacts between Aβ₄₂ monomer and pentapeptides. The secondary structure analysis of the conformational ensembles generated by molecular dynamics (MD) depicted remarkably enhanced sampling of helical and no β-sheet conformations in Aβ₄₂ monomer on the incorporation of RVVPI and RIAPA. Notably, RVVPI and RIAPA destabilized the D23-K28 salt bridge in Aβ₄₂ monomer, which plays a crucial role in Aβ₄₂ oligomer stability and fibril formation. The MD simulations highlighted that the incorporation of proline and arginine in pentapeptides contributed to their strong binding with Aβ₄₂ monomer. Furthermore, RVVPI and RIAPA prevented conformational conversion of Aβ₄₂ monomer to aggregation-prone structures, which, in turn, resulted in a lower aggregation tendency of Aβ₄₂ monomer.