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Updated: Mar 11, 2026
Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
Published on: February 27, 2016
Structure-Guided Optimization and Biological Validation of 1,3,4-Thiadiazole-Based SIRT2 Inhibitors Reinforcing
Ahmet Bugra Aksel1, Fikriye Ozgencil1, Filiz Bakar-Ates2
1Department of Pharmaceutical Chemistry, SIRTeam Group, Faculty of Pharmacy, Gazi University, Ankara, Türkiye.
Abstract:
SIRT2, the cytoplasmic member of the sirtuin family, is generally acknowledged to promote cancer and contribute to the progression of various pathologies, including neurodegeneration, inflammation, obesity, and bacterial infection through the deacetylation of target substrates. In our previous efforts we identified potent and highly selective SIRT2 inhibitors with IC50 values in the micromolar range. To further optimize their activity, we performed molecular docking-guided design and subsequent synthesis of a series of novel 1,3,4-thiadiazole derivatives. SIRT inhibitory screening identified that ST131 and ST132 achieved moderate inhibitory effects against SIRT2 with IC50 values of 8.95 and 6.62 µM, respectively. Moreover, cellular assays in MCF-7 breast cancer cells revealed that ST132 has shown an antiproliferative effect, as well as increased acetylated α-tubulin expression levels, which is typically consistent with SIRT2 inhibition. In addition, docking studies were performed to analyze and rationalize the structural differences responsible for SIRT2 activity, shedding light on the importance of the interactions occurring at the entrance of the binding site. Finally, molecular mechanics-generalized born surface area (MM-GBSA) and molecular dynamics (MD) simulation approaches were conducted to verify the stability of ST132 in the complex with SIRT2.
Insights
Researchers designed novel 1,3,4-thiadiazole derivatives to inhibit SIRT2 (Sirtuin 2), a protein linked to cancer and other diseases. Compound ST132 demonstrated antiproliferative effects in breast cancer cells, validating its potential as a SIRT2 inhibitor.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Molecular Biology
Background:
- Sirtuin 2 (SIRT2) is a deacetylase implicated in cancer progression and various pathologies.
- Previous efforts yielded SIRT2 inhibitors with micromolar activity.
- Optimization of these inhibitors is crucial for therapeutic development.
Purpose of the Study:
- To design and synthesize novel 1,3,4-thiadiazole derivatives as potential SIRT2 inhibitors.
- To evaluate the inhibitory activity and antiproliferative effects of the synthesized compounds.
- To elucidate the structural basis of SIRT2 inhibition using computational methods.
Main Methods:
- Molecular docking-guided drug design.
- Synthesis of 1,3,4-thiadiazole derivatives.
- In vitro SIRT inhibitory screening (IC50 determination).
- Cellular assays in MCF-7 breast cancer cells.
- Molecular dynamics (MD) and MM-GBSA simulations.
Main Results:
- Two compounds, ST131 and ST132, exhibited moderate SIRT2 inhibition (IC50 values of 8.95 and 6.62 µM, respectively).
- ST132 demonstrated antiproliferative activity against MCF-7 cells.
- ST132 treatment led to increased acetylated α-tubulin, a marker of SIRT2 inhibition.
- Computational analyses rationalized the structure-activity relationship and confirmed ST132-SIRT2 complex stability.
Conclusions:
- Novel 1,3,4-thiadiazole derivatives were successfully synthesized and evaluated as SIRT2 inhibitors.
- ST132 shows promising antiproliferative effects and SIRT2 inhibitory activity.
- Computational modeling provided insights into the binding interactions and stability of ST132 with SIRT2, guiding future drug design efforts.
