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...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-09-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/16/9/1316 |
| _version_ | 1797578008840634368 |
|---|---|
| author | Elena Abbotto Beatrice Casini Francesco Piacente Naomi Scarano Elena Cerri Michele Tonelli Cecilia Astigiano Enrico Millo Laura Sturla Santina Bruzzone Elena Cichero |
| author_facet | Elena Abbotto Beatrice Casini Francesco Piacente Naomi Scarano Elena Cerri Michele Tonelli Cecilia Astigiano Enrico Millo Laura Sturla Santina Bruzzone Elena Cichero |
| author_sort | Elena Abbotto |
| collection | DOAJ |
| 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 (<b>1a</b>–<b>7a</b>), 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 <b>2a</b> and <b>7a</b> were found to be the most promising derivatives herein proposed. |
| first_indexed | 2024-03-10T22:16:16Z |
| format | Article |
| id | doaj.art-46865828e47740e4bb165765d251573f |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T22:16:16Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-46865828e47740e4bb165765d251573f2023-11-19T12:25:41ZengMDPI AGPharmaceuticals1424-82472023-09-01169131610.3390/ph16091316Novel Thiazole-Based SIRT2 Inhibitors Discovered via Molecular Modelling Studies and Enzymatic AssaysElena Abbotto0Beatrice Casini1Francesco Piacente2Naomi Scarano3Elena Cerri4Michele Tonelli5Cecilia Astigiano6Enrico Millo7Laura Sturla8Santina Bruzzone9Elena Cichero10Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, ItalyDepartment of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, ItalyDepartment of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, ItalyDepartment of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, ItalyDepartment of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, ItalyDepartment of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, ItalyDepartment of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, ItalyDepartment of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, ItalyDepartment of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, ItalyDepartment of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, ItalyDepartment of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, ItalyRecently, 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 (<b>1a</b>–<b>7a</b>), 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 <b>2a</b> and <b>7a</b> were found to be the most promising derivatives herein proposed.https://www.mdpi.com/1424-8247/16/9/1316SIRT2sirtuinvirtual screeningmolecular dockingenzymatic assaysinhibitor |
| spellingShingle | Elena Abbotto Beatrice Casini Francesco Piacente Naomi Scarano Elena Cerri Michele Tonelli Cecilia Astigiano Enrico Millo Laura Sturla Santina Bruzzone Elena Cichero Novel Thiazole-Based SIRT2 Inhibitors Discovered via Molecular Modelling Studies and Enzymatic Assays Pharmaceuticals SIRT2 sirtuin virtual screening molecular docking enzymatic assays inhibitor |
| 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 | SIRT2 sirtuin virtual screening molecular docking enzymatic assays inhibitor |
| url | https://www.mdpi.com/1424-8247/16/9/1316 |
| work_keys_str_mv | AT elenaabbotto novelthiazolebasedsirt2inhibitorsdiscoveredviamolecularmodellingstudiesandenzymaticassays AT beatricecasini novelthiazolebasedsirt2inhibitorsdiscoveredviamolecularmodellingstudiesandenzymaticassays AT francescopiacente novelthiazolebasedsirt2inhibitorsdiscoveredviamolecularmodellingstudiesandenzymaticassays AT naomiscarano novelthiazolebasedsirt2inhibitorsdiscoveredviamolecularmodellingstudiesandenzymaticassays AT elenacerri novelthiazolebasedsirt2inhibitorsdiscoveredviamolecularmodellingstudiesandenzymaticassays AT micheletonelli novelthiazolebasedsirt2inhibitorsdiscoveredviamolecularmodellingstudiesandenzymaticassays AT ceciliaastigiano novelthiazolebasedsirt2inhibitorsdiscoveredviamolecularmodellingstudiesandenzymaticassays AT enricomillo novelthiazolebasedsirt2inhibitorsdiscoveredviamolecularmodellingstudiesandenzymaticassays AT laurasturla novelthiazolebasedsirt2inhibitorsdiscoveredviamolecularmodellingstudiesandenzymaticassays AT santinabruzzone novelthiazolebasedsirt2inhibitorsdiscoveredviamolecularmodellingstudiesandenzymaticassays AT elenacichero novelthiazolebasedsirt2inhibitorsdiscoveredviamolecularmodellingstudiesandenzymaticassays |