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

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Jun 10

PMID 37298312

Authors

Naomi Scarano

Elena Abbotto

Francesca Musumeci

Annalisa Salis

Chiara Brullo

Paola Fossa

Silvia Schenone

Santina Bruzzone

Elena Cichero

Affiliations

Soon will be listed here.

Abstract

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 (-). 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.

Citing Articles

Discovery of Novel Thiazole-Based SIRT2 Inhibitors as Anticancer Agents: Molecular Modeling, Chemical Synthesis and Biological Assays.

Piacente F, Guccione G, Scarano N, Lunaccio D, Miro C, Abbotto E Int J Mol Sci. 2024; 25(20).

PMID: 39456864 PMC: 11508362. DOI: 10.3390/ijms252011084.

Recent Advances in the Discovery of SIRT1/2 Inhibitors via Computational Methods: A Perspective.

Scarano N, Brullo C, Musumeci F, Millo E, Bruzzone S, Schenone S Pharmaceuticals (Basel). 2024; 17(5).

PMID: 38794171 PMC: 11123952. DOI: 10.3390/ph17050601.

In Silico and In Vitro Evaluation of the Mechanism of Action of Three VX809-Based Hybrid Derivatives as Correctors of the F508del CFTR Protein.

Baroni D, Scarano N, Ludovico A, Brandas C, Parodi A, Lunaccio D Pharmaceuticals (Basel). 2023; 16(12).

PMID: 38139828 PMC: 10748060. DOI: 10.3390/ph16121702.

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

Abbotto E, Casini B, Piacente F, Scarano N, Cerri E, Tonelli M Pharmaceuticals (Basel). 2023; 16(9).

PMID: 37765125 PMC: 10535842. DOI: 10.3390/ph16091316.

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