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Virtual Screening Combined with Enzymatic Assays to Guide the Discovery of Novel SIRT2 Inhibitors

Sirtuin isoform 2 (SIRT2) is one of the seven sirtuin isoforms present in humans, being classified as class III histone deacetylases (HDACs). Based on the high sequence similarity among SIRTs, the identification of isoform selective modulators represents a challenging task, especially for the high c...

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Autores principales: Scarano, Naomi, Abbotto, Elena, Musumeci, Francesca, Salis, Annalisa, Brullo, Chiara, Fossa, Paola, Schenone, Silvia, 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/PMC10253774/
https://www.ncbi.nlm.nih.gov/pubmed/37298312
http://dx.doi.org/10.3390/ijms24119363
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author Scarano, Naomi
Abbotto, Elena
Musumeci, Francesca
Salis, Annalisa
Brullo, Chiara
Fossa, Paola
Schenone, Silvia
Bruzzone, Santina
Cichero, Elena
author_facet Scarano, Naomi
Abbotto, Elena
Musumeci, Francesca
Salis, Annalisa
Brullo, Chiara
Fossa, Paola
Schenone, Silvia
Bruzzone, Santina
Cichero, Elena
author_sort Scarano, Naomi
collection PubMed
description Sirtuin isoform 2 (SIRT2) is one of the seven sirtuin isoforms present in humans, being classified as class III histone deacetylases (HDACs). Based on the high sequence similarity among SIRTs, the identification of isoform selective modulators represents a challenging task, especially for the high conservation observed in the catalytic site. Efforts in rationalizing selectivity based on key residues belonging to the SIRT2 enzyme were accompanied in 2015 by the publication of the first X-ray crystallographic structure of the potent and selective SIRT2 inhibitor SirReal2. The subsequent studies led to different experimental data regarding this protein in complex with further different chemo-types as SIRT2 inhibitors. Herein, we reported preliminary Structure-Based Virtual Screening (SBVS) studies using a commercially available library of compounds to identify novel scaffolds for the design of new SIRT2 inhibitors. Biochemical assays involving five selected compounds allowed us to highlight the most effective chemical features supporting the observed SIRT2 inhibitory ability. This information guided the following in silico evaluation and in vitro testing of further compounds from in-house libraries of pyrazolo-pyrimidine derivatives towards novel SIRT2 inhibitors (1–5). The final results indicated the effectiveness of this scaffold for the design of promising and selective SIRT2 inhibitors, featuring the highest inhibition among the tested compounds, and validating the applied strategy.
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spelling pubmed-102537742023-06-10 Virtual Screening Combined with Enzymatic Assays to Guide the Discovery of Novel SIRT2 Inhibitors Scarano, Naomi Abbotto, Elena Musumeci, Francesca Salis, Annalisa Brullo, Chiara Fossa, Paola Schenone, Silvia Bruzzone, Santina Cichero, Elena Int J Mol Sci Article Sirtuin isoform 2 (SIRT2) is one of the seven sirtuin isoforms present in humans, being classified as class III histone deacetylases (HDACs). Based on the high sequence similarity among SIRTs, the identification of isoform selective modulators represents a challenging task, especially for the high conservation observed in the catalytic site. Efforts in rationalizing selectivity based on key residues belonging to the SIRT2 enzyme were accompanied in 2015 by the publication of the first X-ray crystallographic structure of the potent and selective SIRT2 inhibitor SirReal2. The subsequent studies led to different experimental data regarding this protein in complex with further different chemo-types as SIRT2 inhibitors. Herein, we reported preliminary Structure-Based Virtual Screening (SBVS) studies using a commercially available library of compounds to identify novel scaffolds for the design of new SIRT2 inhibitors. Biochemical assays involving five selected compounds allowed us to highlight the most effective chemical features supporting the observed SIRT2 inhibitory ability. This information guided the following in silico evaluation and in vitro testing of further compounds from in-house libraries of pyrazolo-pyrimidine derivatives towards novel SIRT2 inhibitors (1–5). The final results indicated the effectiveness of this scaffold for the design of promising and selective SIRT2 inhibitors, featuring the highest inhibition among the tested compounds, and validating the applied strategy. MDPI 2023-05-27 /pmc/articles/PMC10253774/ /pubmed/37298312 http://dx.doi.org/10.3390/ijms24119363 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
Scarano, Naomi
Abbotto, Elena
Musumeci, Francesca
Salis, Annalisa
Brullo, Chiara
Fossa, Paola
Schenone, Silvia
Bruzzone, Santina
Cichero, Elena
Virtual Screening Combined with Enzymatic Assays to Guide the Discovery of Novel SIRT2 Inhibitors
title Virtual Screening Combined with Enzymatic Assays to Guide the Discovery of Novel SIRT2 Inhibitors
title_full Virtual Screening Combined with Enzymatic Assays to Guide the Discovery of Novel SIRT2 Inhibitors
title_fullStr Virtual Screening Combined with Enzymatic Assays to Guide the Discovery of Novel SIRT2 Inhibitors
title_full_unstemmed Virtual Screening Combined with Enzymatic Assays to Guide the Discovery of Novel SIRT2 Inhibitors
title_short Virtual Screening Combined with Enzymatic Assays to Guide the Discovery of Novel SIRT2 Inhibitors
title_sort virtual screening combined with enzymatic assays to guide the discovery of novel sirt2 inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10253774/
https://www.ncbi.nlm.nih.gov/pubmed/37298312
http://dx.doi.org/10.3390/ijms24119363
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