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Novel Thiazole-Based SIRT2 Inhibitors Discovered via Molecular Modelling Studies and Enzymatic Assays

Recently, the development of sirtuin small molecule inhibitors (SIRTIs) has been gaining attention for the treatment of different cancer types, but also to contrast neurodegenerative disease, diabetes, and autoimmune syndromes. In the search for SIRT2 modulators, the availability of several X-crysta...

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Autores principales: Abbotto, Elena, Casini, Beatrice, Piacente, Francesco, Scarano, Naomi, Cerri, Elena, Tonelli, Michele, Astigiano, Cecilia, Millo, Enrico, Sturla, Laura, Bruzzone, Santina, Cichero, Elena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10535842/
https://www.ncbi.nlm.nih.gov/pubmed/37765125
http://dx.doi.org/10.3390/ph16091316
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author Abbotto, Elena
Casini, Beatrice
Piacente, Francesco
Scarano, Naomi
Cerri, Elena
Tonelli, Michele
Astigiano, Cecilia
Millo, Enrico
Sturla, Laura
Bruzzone, Santina
Cichero, Elena
author_facet Abbotto, Elena
Casini, Beatrice
Piacente, Francesco
Scarano, Naomi
Cerri, Elena
Tonelli, Michele
Astigiano, Cecilia
Millo, Enrico
Sturla, Laura
Bruzzone, Santina
Cichero, Elena
author_sort Abbotto, Elena
collection PubMed
description Recently, the development of sirtuin small molecule inhibitors (SIRTIs) has been gaining attention for the treatment of different cancer types, but also to contrast neurodegenerative disease, diabetes, and autoimmune syndromes. In the search for SIRT2 modulators, the availability of several X-crystallographic data regarding SIRT2−ligand complexes has allowed for setting up a structure-based study, which is herein presented. A set of 116 SIRT2 inhibitors featuring different chemical structures has been collected from the literature and used for molecular docking studies involving 4RMG and 5MAT PDB codes. The information found highlights key contacts with the SIRT2 binding pocket such as Van der Waals and π–π stacking with Tyr104, Phe119, Phe234, and Phe235 in order to achieve high inhibitory ability values. Following the preliminary virtual screening studies, a small in-house library of compounds (1a–7a), previously investigated as putative HSP70 inhibitors, was described to guide the search for dual-acting HSP70/SIRT2 inhibitors. Biological and enzymatic assays validated the whole procedure. Compounds 2a and 7a were found to be the most promising derivatives herein proposed.
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spelling pubmed-105358422023-09-29 Novel Thiazole-Based SIRT2 Inhibitors Discovered via Molecular Modelling Studies and Enzymatic Assays Abbotto, Elena Casini, Beatrice Piacente, Francesco Scarano, Naomi Cerri, Elena Tonelli, Michele Astigiano, Cecilia Millo, Enrico Sturla, Laura Bruzzone, Santina Cichero, Elena Pharmaceuticals (Basel) Article Recently, the development of sirtuin small molecule inhibitors (SIRTIs) has been gaining attention for the treatment of different cancer types, but also to contrast neurodegenerative disease, diabetes, and autoimmune syndromes. In the search for SIRT2 modulators, the availability of several X-crystallographic data regarding SIRT2−ligand complexes has allowed for setting up a structure-based study, which is herein presented. A set of 116 SIRT2 inhibitors featuring different chemical structures has been collected from the literature and used for molecular docking studies involving 4RMG and 5MAT PDB codes. The information found highlights key contacts with the SIRT2 binding pocket such as Van der Waals and π–π stacking with Tyr104, Phe119, Phe234, and Phe235 in order to achieve high inhibitory ability values. Following the preliminary virtual screening studies, a small in-house library of compounds (1a–7a), previously investigated as putative HSP70 inhibitors, was described to guide the search for dual-acting HSP70/SIRT2 inhibitors. Biological and enzymatic assays validated the whole procedure. Compounds 2a and 7a were found to be the most promising derivatives herein proposed. MDPI 2023-09-18 /pmc/articles/PMC10535842/ /pubmed/37765125 http://dx.doi.org/10.3390/ph16091316 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Abbotto, Elena
Casini, Beatrice
Piacente, Francesco
Scarano, Naomi
Cerri, Elena
Tonelli, Michele
Astigiano, Cecilia
Millo, Enrico
Sturla, Laura
Bruzzone, Santina
Cichero, Elena
Novel Thiazole-Based SIRT2 Inhibitors Discovered via Molecular Modelling Studies and Enzymatic Assays
title Novel Thiazole-Based SIRT2 Inhibitors Discovered via Molecular Modelling Studies and Enzymatic Assays
title_full Novel Thiazole-Based SIRT2 Inhibitors Discovered via Molecular Modelling Studies and Enzymatic Assays
title_fullStr Novel Thiazole-Based SIRT2 Inhibitors Discovered via Molecular Modelling Studies and Enzymatic Assays
title_full_unstemmed Novel Thiazole-Based SIRT2 Inhibitors Discovered via Molecular Modelling Studies and Enzymatic Assays
title_short Novel Thiazole-Based SIRT2 Inhibitors Discovered via Molecular Modelling Studies and Enzymatic Assays
title_sort novel thiazole-based sirt2 inhibitors discovered via molecular modelling studies and enzymatic assays
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10535842/
https://www.ncbi.nlm.nih.gov/pubmed/37765125
http://dx.doi.org/10.3390/ph16091316
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