The binding of small carbazole derivative (P7C3) to protofibrils of the Alzheimer's disease and β-secretase: Molecular dynamics simulation studies

The molecular basis of Alzheimer's disease (AD) is a critical aspect for understanding the role of A beta fibrils in neurotoxicity and for designing therapeutic strategies against AD. Molecular insight into the prevention of A beta peptide aggregates in the presence of P7C3, a derivative of dibromocarbazole, molecule is presented for the first time. P7C3 protects newborn neurons from apoptotic cell death, but mechanistic details are lacking. The ability of P7C3 to prevent the onset or to slow the progression of the Alzheimer's disease was studied by using molecular dynamics (MD) simulations. Two different mechanisms were considered: the disruption of A beta aggregation by direct binding of P7C3 to A beta and alterations in amyloid precursor protein processing through the inhibition of beta-secretase. The results indicate that P7C3 molecule can efficiently bind to the beta-secretase active site. The direct interactions of P7C3 with A beta peptide are also important but in a lesser extent. (C) 2015 Elsevier B.V. All rights reserved.