Abstract
Sirtuins (class III histone deacetylase) are evolutionarily conserved NAD+-dependent enzymes that catalyze the deacetylation of acetyl-lysine residues of histones and other target proteins. Because of their associations in various pathophysiological conditions, the identification of small molecule modulators has been of significant interest. In the present study, virtual screening was carried out with NCI Diversity Set II using crystal structure of hSIRT2 (PDB ID: 1J8F) as a model for the docking procedure to find potential compounds, which were then subjected to experimental tests for their in vitro SIRT2 inhibitory activity. One of the 40 compounds tested, NSC671136 (IUPAC name: 6-Acetyl-4-oxo-1,3-diphenyl-2-thioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl 2,4-dichlorobenzoate) has structurally unique scaffold, showed strong inhibitory activity towards SIRT2 with IC50 of ~8.7 μM and to a lesser extent on SIRT1 activity. The reported compound is substantially potent compared to the published SIRT2 inhibitors and serves as an excellent base for future lead development.
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Acknowledgments
We thank Drs. Javed Iqbal and Devyani Haldar for allowed us to utilize their biological facilities as well as for their constant support during our experimental work at Institute of Life Sciences (ILS, a not-for-profit organization), University of Hyderabad campus, Gachibowli, Hyderabad.
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Padavattan Sivaraman and Suresh Mattegunta contributed equally to this work.
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Sivaraman, P., Mattegunta, S., Subbaraju, G.V. et al. Design of a novel nucleoside analog as potent inhibitor of the NAD+ dependent deacetylase, SIRT2. Syst Synth Biol 4, 257–263 (2010). https://doi.org/10.1007/s11693-011-9069-4
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DOI: https://doi.org/10.1007/s11693-011-9069-4