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An arginine-rich peptide inhibits AChE: template-based design, molecular modeling, synthesis, and biological evaluation

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Abstract

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 (Aβ) 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 Aβ 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 μM. 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.

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Data were reported in the manuscript as much as possible, and other materials will be available via request to the corresponding author.

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Acknowledgements

We would like to thank the Research and Technology Vice-chancellor of Hamadan University of Medical Sciences for financial support.

Funding

This research was funded by Vice-chancellor for Research and Technology, Hamadan University of Medical Sciences (No. 9604132260).

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Authors and Affiliations

  1. Department of Pharmacognosy, School of Pharmacy, Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran

    Dara Dastan

  2. Department of Medicinal Chemistry, School of Pharmacy, Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran

    Reza Zhiyani, Kiana Fasihi & Ahmad Ebadi

Authors
  1. Dara Dastan
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  2. Reza Zhiyani
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  3. Kiana Fasihi
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  4. Ahmad Ebadi
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Contributions

The initial idea about a peptidic inhibitors of PAS in AChE was conceived by AE. Accordingly, AE and DD hypothesized the problem and designed the study. AE, RZ and KF performed all the calculations. RZ and KF synthesized the peptide and evaluated the AChE inhibitory effect. AE and DD contributed with results, discussions, and especially during the revision. RZ and KF drafted most of the basic structure of the introduction and methods. AE wrote the main draft of the paper with active help primarily from DD and rigorously revised the paper until satisfactory. All authors have read and approved the final manuscript.

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Correspondence to Ahmad Ebadi.

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Dastan, D., Zhiyani, R., Fasihi, K. et al. An arginine-rich peptide inhibits AChE: template-based design, molecular modeling, synthesis, and biological evaluation. J Mol Model 28, 86 (2022). https://doi.org/10.1007/s00894-022-05058-2

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