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-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 & pi;-& pi; 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.

Automated summary

This study focuses on the development of SIRT2 small molecule inhibitors and utilizes a structure-based approach to identify the most effective inhibitors. Molecular docking studies were conducted using 116 SIRT2 inhibitors with different chemical structures, and the results were validated through biological and enzymatic assays. Compounds 2a and 7a were found to be the most promising derivatives.