Dastan_2022_J.Mol.Model_28_86

Life expectancy is growing especially in developed countries. In this regard, aging-associated diseases such as Alzheimer's disease (AD) are more common. Multi interconnected pathological factors involved in AD demand multi-target therapeutics. AChE, as a well-known target in AD, decreases the acetylcholine (ACh) in cholinergic synapse and, besides, increases the rate of amyloid-beta (Abeta) aggregation. To block the destructive effects of AChE on cholinergic neurons in AD, we designed a peptidic inhibitor of the peripheral anionic site (PAS). The PAS plays a crucial role to attract and direct the ACh to the enzyme active site and increase the rate of Abeta aggregation by changing the folding state. We utilized the template-based approach in combination with molecular docking, molecular dynamic simulation, and data mining to design a peptide library. Scoring was performed according to binding energy and the interaction profile of AChE inhibitors. The best candidate (p8, RMLRTTRY) was synthesized using solid-phase peptide synthesis, purified by RP-HPLC, and identified by ESI-MS. The inhibitory effect of p8 on AChE was 102.2 +/- 15.2 microM. The kinetic and molecular modeling studies indicated the mixed inhibition mechanism for p8. The Arg residues in p8 had an essential role in binding to PAS.