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Structure‐Based Virtual Screening and in vitro and in vivo Analyses Revealed Potent Methyltransferase G9a Inhibitors as Prospective Anti‐Alzheimer's Agents
Author(s) -
BellverSanchis Aina,
Singh Choudhary Bhanwar,
CompanysAlemany Júlia,
ÁvilaLópez Pedro A.,
Martínez Rodríguez Antón Leandro,
Brea Floriani Jose Manuel,
Malik Ruchi,
Pallàs Mercè,
Pérez Belén,
GriñánFerré Christian
Publication year - 2022
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202200002
Subject(s) - virtual screening , epigenetics , methyltransferase , histone methyltransferase , in vivo , biology , alzheimer's disease , caenorhabditis elegans , histone h3 , transgene , drug discovery , pharmacology , microbiology and biotechnology , biochemistry , genetics , gene , medicine , disease , methylation , pathology
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.