From Venom to AChE Inhibitor: Design, Molecular Modeling, and Synthesis of a Peptidic Inhibitor of AChE

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Alzheimer’s disease (AD) is an irreversible and progressive brain disorder that slowly destroys memory and cognitive skills. The current treatment of AD mainly focused on the restoring of ACh levels through acetylcholinesterase (AChE) inhibition. Peptides are a unique class of pharmaceutical compounds that have privilege over small molecules, especially in the realm of protein–protein interactions and G protein-coupled receptor (GPCR) inhibitors. We applied a rational structure-based virtual design approach to discover new peptidic inhibitors of AChE. In this regard, conformational space in the fasciculin II (Fas) and AChE complex was evaluated utilizing MD simulation, principal component analysis and clustering to figure out possible interactions of Fas and AChE. Assessment of Fas–AChE interactions by visual evaluation and alanine scanning led to the design of 10 peptides. The highest scored peptide (p2) was selected and synthesized using SPPS. Based on Ellman's test, the inhibitory activity of p2 against AChE was 51.2 ± 8.1 µM. The kinetics study of the enzyme inhibition in accompany with molecular modeling results revealed that p2 was a mixed-type reversible inhibitor of AChE. The DNRMLRTTRY peptide was considerable inhibitor of AChE. Peptides have the merit of being big enough to inhibit PPI and GPCR class B with a wide binding site. But possible peptidic chemical space is too large to be evaluated by the classical peptide synthesis methods. In the present contribution, we introduced a rational in silico peptide design approach that led to the considerable peptidic inhibitor of AChE.