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

Abstract

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.

Exploring the Therapeutic Potential of Ammodaucus leucotrichus Seed Extracts: A Multi-Faceted Analysis of Phytochemical Composition, Anti-Inflammatory Efficacy, Predictive Anti-Arthritic Properties, and Molecular Docking Insights

“…The high trypsin inhibition by the methanol extract suggests considerable anti-inflammatory effects, as reported by Biswajita, P et al [ 45 ] and Mane, M. P et al [ 46 ] using other plant extracts (Enteromorpha intestinalis and Polygala arvensis). Protease inhibitors have demonstrated efficacy in various clinical diseases, including cancer, AIDS, RA, pancreatitis, and thrombosis [ 47 ]. Therefore, the methanol extract holds promise for RA by effectively inhibiting proteases, offering a natural alternative approach to diclofenac, a non-steroidal anti-inflammatory drug with important side effects.…”

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

“…Recently, Abbotto reported structure-based studies performed based on the X-ray data of 4RMG and 5MAT, where the focus was on the (flexible) SirReal2 chemo-type and (rigid) thieno-pyrimidinone scaffold. The results allowed for guiding the in silico screening of further thiazoles (26,27) that exhibited SIRT2 inhibitor behavior [97]. Indeed, preliminary in silico screening at both 4RMG and 5MAT, while maintaining the protein binding site as rigid or flexible, led to comparable docking poses with those of the co-crystallized ligand experimental data.…”

“…Subsequent structure-based studies on in-house compounds have led to the identification of thiazole-containing derivatives exhibiting SIRT2 inhibitory ability and selectivity toward SIRT6 [97]. The most effective one (Table 5, Entry 7) resulted in a good SIRT2I (IC 50 = 17.3 µM).…”

“…Benzofuran derivatives [124] Thienopyrimidinone compounds [56] Benzothiadiazine-1,1-dioxide-based compounds [125] Cambinol-related compounds [126] Piperine-resveratrol compounds [127] Nicotinamide-containing compounds [128] Pyrazolo-pyrimidine derivatives [66] Thiazole-based compounds [97] Xanthone derivatives [129] Cysteamine derivatives [130] Dual SIRT1/2Is…”

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

“…All the molecular docking calculations have been performed, applying the DOCK tool implemented in MOE based on the template similarity methodology, including all those amino acids placed at 4.5 Å distance from the PDB ligand in the experimental conformation. Details of the docking procedure have been previously described by us [58,59].…”