and Determination of Glutaminyl Cyclase Inhibitors

Overview

Journal RSC Adv

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2022 May 9

PMID 35531555

Authors

Phuong-Thao Tran

Van-Hai Hoang

Jeewoo Lee

Tran Thi Thu Hien

Nguyen Thanh Tung

Son Tung Ngo

Affiliations

Soon will be listed here.

Abstract

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--(3-(5-methyl-1-imidazol-1-yl)propyl)-1-benzo[]imidazol-2-amine (1_2) was indicated as a potential drug for AD treatment.

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