Tahmasebi_2020_Bioorg.Chem_105_104351

The prevalence of Alzheimer's disease (AD) has become a substantial global concern. Approved AChE inhibitors have been used for symptomatic treatment of AD. Binding of amyloid beta (Abeta) to the peripheral anionic site of AChE facilitates the formation of Abeta plaques. Blocking this proposed protein-protein interaction by inhibition of the peripheral anionic site of AChE, in addition to increasing the level of ACh, reduces the Abeta aggregation and might qualify to slow down the progression of disease besides the palliative treatment. Targeting protein-protein interactions consider as one of the most challenging issues in the realm of drug design in which peptides have potentials to excel in. In the present study, we applied two virtual fragment-based and template-based approaches to design peptidic inhibitors of the PAS of AChE. Based on the in silico studies, high scored peptides p2 (WTWYGYWVW) and p10 (NHRMLTRRY) obtained from fragment-based and template-based design respectively. Regarding in vitro results, p2 (IC(50) = 16 +/- 3.2 muM) and p10 (IC(50) = 23.6 +/- 4.9 muM) showed significant AChE inhibitory effects. The molecular mechanism of inhibition studied by Lineweaver-Burk plots was mixed inhibition for both peptides. The in vitro results conformed to the in silico results and showed that both peptides occupied the CAS and PAS of AChE. The comparison of two peptide-design approaches revealed that the fragment-based design had more chemical diversity and showed priority to the template-based design. According to the obtained results, peptidic inhibitors of AChE designed by the proposed fragment-based approach might be more efficient in comparison to traditional approaches.