Issue 51, 2019, Issue in Progress

In vitro and in silico determination of glutaminyl cyclase inhibitors


Alzheimer's disease (AD) is the most common form of neurodegenerative disease currently. It is widely accepted that AD is characterized by the self-assembly of amyloid beta (Aβ) peptides. The human glutaminyl cyclase (hQC) enzyme is characterized by association with Aβ peptide generation. The development of hQC inhibitors could prevent the self-aggregation of Aβ peptides, resulting in impeding AD. Utilizing structural knowledge of the hQC substrates and known hQC inhibitors, new heterocyclic and peptidomimetic derivatives were synthesized and were able to inhibit the hQC enzyme. The inhibiting abilities of these compounds were evaluated using a fluorometric assay. The binding mechanism at the atomic level was estimated using molecular docking, free energy perturbation, and quantum chemical calculation methods. The predicted log(BBB) and human intestinal absorption values indicated that these compounds are able to permeate the blood–brain barrier and be well-absorbed through the gastrointestinal tract. Overall, 5,6-dimethoxy-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1H-benzo[d]imidazol-2-amine (1_2) was indicated as a potential drug for AD treatment.

Graphical abstract: In vitro and in silico determination of glutaminyl cyclase inhibitors

Supplementary files

Article information

Article type
25 Jul 2019
13 Sep 2019
First published
19 Sep 2019
This article is Open Access
Creative Commons BY license

RSC Adv., 2019,9, 29619-29627

In vitro and in silico determination of glutaminyl cyclase inhibitors

P. Tran, V. Hoang, J. Lee, T. T. T. Hien, N. T. Tung and S. T. Ngo, RSC Adv., 2019, 9, 29619 DOI: 10.1039/C9RA05763C

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