Structure-Based Virtual Screening and in vitro and in vivo Analyses Revealed Potent Methyltransferase G9a Inhibitors as Prospective Anti-Alzheimer's Agents
Bellver-Sanchis, Aina (Universitat de Barcelona)
Singh Choudhary, Bhanwar (Ganpat University)
Companys-Alemany, Júlia (Universitat de Barcelona)
Sukanya, None (Central University of Rajasthan)
Ávila-López, Pedro A. (Northwestern University)
Martínez Rodríguez, Antón Leandro (Universidade de Santiago de Compostela)
Brea Floriani, Jose Manuel (Universidade de Santiago de Compostela)
Malik, Ruchi (Central University of Rajasthan)
Pallàs, Mercè (Universitat de Barcelona)
Pérez, Belén (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Griñán-Ferré, Christian (Universitat de Barcelona)

Date:	2022
Abstract:	G9a is a lysine methyltransferase able to di-methylate lysine 9 of histone H3, promoting the repression of genes involved in learning and memory. Novel strategies based on synthesizing epigenetic drugs could regulate gene expression through histone post-translational modifications and effectively treat neurodegenerative diseases, like Alzheimer's disease (AD). Here, potential G9a inhibitors were identified using a structure-based virtual screening against G9a, followed by in vitro and in vivo screenings. First, screening methods with the AD transgenic Caenorhabditis elegans strain CL2006, showed that the toxicity/function range was safe and recovered age-dependent paralysis. Likewise, we demonstrated that the best candidates direct target G9a by reducing H3 K9me2 in the CL2006 strain. Further characterization of these compounds involved the assessment of the blood-brain barrier-permeability and impact on amyloid-β aggregation, showing promising results. Thus, we present a G9a inhibitor candidate, F, with a novel and potent structure, providing both leads in G9a inhibitor design and demonstrating their participation in reducing AD pathology. Epigenetic modifications : A structure-based virtual screen led to the identification of new scaffolds as potent G9a inhibitors. These promising hits exhibited better in silico profiles, IC values, and BBB permeability than currently published inhibitors for G9a. The best G9a inhibitor candidates directly target G9a, decreasing the levels of the repressive mark H3 K9me2 (demethylation of H3 K9), and beneficial effects on amyloid aggregation were observed in C. elegans.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Alzheimer's disease ; Amyloid-β ; Epigenetics ; G9a methyltransferase ; Structure based virtual screening
Published in:	ChemMedChem, Vol. 17 (may 2022) , ISSN 1860-7187

DOI: 10.1002/cmdc.202200002
PMID: 35413149

10 p, 2.1 MB

The record appears in these collections:
Articles > Research articles
Articles > Published articles