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Updated: May 5, 2026
NMR-Based Fragment Screening in a Minimum Sample but Maximum Automation Mode
Published on: June 4, 2021
In silico-guided exploration of SIRT6 modulation: Discovery of new fragments hits inhibitors
Ignazio Sardo1, Giulia Culletta1, Ugo Perricone2
1Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123, Palermo, Italy.
Abstract:
Sirtuin 6 (SIRT6) has recently gained significant attention due to its dual role in various cancers and its involvement in crucial biological processes such as DNA damage repair, telomere maintenance, and metabolic regulation. Despite this, selective modulation of SIRT6 remains challenging, particularly regarding developing potent inhibitors. This study involved a combination of computational approaches to gain insights into the molecular mechanism of action of SIRT6 and try to identify new potential inhibitors through a virtual screening of over 25,000 molecules. We examined the structural interactions of known SIRT6 modulators using docking, molecular dynamics simulations, and binding pose metadynamics. Due to the recent findings on the SIRT6 inhibition in cancer and inflammatory diseases, we focused our attention on the inhibitors. After a structural study of the target, a fragment virtual screening (VS) allowed us to select a set of promising compounds to validate in vitro. Compounds 9, 10, and 13 were the most suitable for a fragment-growth strategy, paving the way for the design and synthesis of new anticancer agents targeting SIRT6.
Insights
Researchers explored Sirtuin 6 (SIRT6) inhibitors for cancer therapy. Computational methods identified promising compounds, including 9, 10, and 13, for developing novel anticancer agents targeting SIRT6.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Chemistry
Background:
- Sirtuin 6 (SIRT6) plays a critical role in DNA repair, telomere maintenance, and metabolism.
- SIRT6's dual role in cancer and the challenge of developing selective inhibitors necessitate further research.
Purpose of the Study:
- To investigate the molecular mechanism of SIRT6.
- To identify novel SIRT6 inhibitors for potential anticancer applications through virtual screening.
Main Methods:
- Docking, molecular dynamics simulations, and binding pose metadynamics were used to analyze SIRT6 structural interactions.
- Fragment virtual screening of over 25,000 molecules was performed to identify potential inhibitors.
- Promising compounds were selected for in vitro validation and fragment-growth strategies.
Main Results:
- Computational analysis provided insights into SIRT6's molecular mechanism.
- Virtual screening identified several potential SIRT6 inhibitors.
- Compounds 9, 10, and 13 emerged as the most promising candidates for further development.
Conclusions:
- The study successfully identified potential SIRT6 inhibitors using computational approaches.
- These findings pave the way for designing and synthesizing new anticancer agents targeting SIRT6.
- Further in vitro validation is warranted for the identified compounds.
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