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Hit Identification and Functional Validation of Novel Dual Inhibitors of HDAC8 and Tubulin Identified by Combining Docking and Molecular Dynamics Simulations

Authors :
Antonio Curcio
Roberta Rocca
Federica Chiera
Maria Eugenia Gallo Cantafio
Ilenia Valentino
Ludovica Ganino
Pierpaolo Murfone
Angela De Simone
Giulia Di Napoli
Stefano Alcaro
Nicola Amodio
Anna Artese
Source :
Antioxidants, Vol 13, Iss 11, p 1427 (2024)
Publication Year :
2024
Publisher :
MDPI AG, 2024.

Abstract

Chromatin organization, which is under the control of histone deacetylases (HDACs), is frequently deregulated in cancer cells. Amongst HDACs, HDAC8 plays an oncogenic role in different neoplasias by acting on both histone and non-histone substrates. Promising anti-cancer strategies have exploited dual-targeting drugs that inhibit both HDAC8 and tubulin. These drugs have shown the potential to enhance the outcome of anti-cancer treatments by simultaneously targeting multiple pathways critical to disease onset and progression. In this study, a structure-based virtual screening (SBVS) of 96403 natural compounds was performed towards the four Class I HDAC isoforms and tubulin. Using molecular docking and molecular dynamics simulations (MDs), we identified two molecules that could selectively interact with HDAC8 and tubulin. CNP0112925 (arundinin), bearing a polyphenolic structure, was confirmed to inhibit HDAC8 activity and tubulin organization, affecting breast cancer cell viability and triggering mitochondrial superoxide production and apoptosis.

Details

Language :
English
ISSN :
20763921
Volume :
13
Issue :
11
Database :
Directory of Open Access Journals
Journal :
Antioxidants
Publication Type :
Academic Journal
Accession number :
edsdoj.f8c2c5113de4980b00d0e871c563cf0
Document Type :
article
Full Text :
https://doi.org/10.3390/antiox13111427