Comparative and pharmacophore model for deacetylase SIRT1

Huhtiniemi, Tero; Wittekindt, Carsten; Laitinen, Tuomo; Leppänen, Jukka; Salminen, Antero; Poso, Antti; Lahtela‐Kakkonen, Maija

doi:10.1007/s10822-006-9084-9

Cited by 47 publications

(42 citation statements)

References 40 publications

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“…However, this is retained by Salermide, suggesting that this drug could constitute a better inhibitor than sirtinol, as earlier experiments showed that Q167 is crucial for HDAC-Sirt2 activity (Finnin et al, 2001). In addition, it is noted that these key binding residues also match one of those reported for EX527 and Sirt1, Q345 (Q167 correspondingly on Sirt2) (Huhtiniemi et al, 2006). Quantification of their corresponding interactions with Sirt2, docking fitness function and a more detailed analysis after energy minimization suggests that Salermide-the stronger inhibitor-may have a higher binding affinity than sirtinol.…”

Section: Resultssupporting

confidence: 58%

“…The available experimental information was considered to define the docking area to be explored; thus, the docking region used was a 10-Å sphere around the oxygen O of Gln167, the Sirt2 C-pocket (Finnin et al, 2001;Min et al, 2001;Avalos et al, 2005;Huhtiniemi et al, 2006). For Salermide, all proposed solutions converged to the same binding area and mode, involving the same residues; however, different solutions emerged for sirtinol, and the five highest-ranking solutions were selected for further analyses.…”

Section: D Modellingmentioning

confidence: 99%

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Salermide, a Sirtuin inhibitor with a strong cancer-specific proapoptotic effect

et al. 2008

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Section: Resultssupporting

confidence: 58%

Section: D Modellingmentioning

confidence: 99%

Salermide, a Sirtuin inhibitor with a strong cancer-specific proapoptotic effect

et al. 2008

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“…For example, although our results provide qualitative comparisons with a recent report by Lara et al (28), the precise binding modes of the inhibitors differ. Moreover, computational studies by Huhtiniemi et al (39) suggest that the conformational freedom of the "flexible loop" region of the C-pocket may play a crucial role in substrate binding, something that is not taken into account using static docking techniques.…”

Section: Discussionmentioning

confidence: 99%

SIRT Inhibitors Induce Cell Death and p53 Acetylation through Targeting Both SIRT1 and SIRT2

Peck

Chen

et al. 2010

Molecular Cancer Therapeutics

390

332

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SIRT proteins play an important role in the survival and drug resistance of tumor cells, especially during chemotherapy. In this study, we investigated the potency, specificity, and cellular targets of three SIRT inhibitors, Sirtinol, Salermide, and EX527. Cell proliferative and cell cycle analyses showed that Sirtinol and Salermide, but not EX527, were effective in inducing cell death at concentrations of 50 μmol/L or over in MCF-7 cells. Instead, EX527 caused cell cycle arrest at G 1 at comparable concentrations. In vitro SIRT assays using a p53 peptide substrate showed that all three compounds are potent SIRT1/2 inhibitors, with EX527 having the highest inhibitory activity for SIRT1. Computational docking analysis showed that Sirtinol and Salermide have high degrees of selectivity for SIRT1/2, whereas EX527 has high specificity for SIRT1 but not SIRT2. Consistently, Sirtinol and Salermide, but not EX527, treatment resulted in the in vivo acetylation of the SIRT1/2 target p53 and SIRT2 target tubulin in MCF-7 cells, suggesting that EX527 is ineffective in inhibiting SIRT2 and that p53 mediates the cytotoxic function of Sirtinol and Salermide. Studies using breast carcinoma cell lines and p53-deficient mouse fibroblasts confirmed that p53 is essential for the Sirtinol and Salermideinduced apoptosis. Further, we showed using small interfering RNA that silencing both SIRTs, but not SIRT1 and SIRT2 individually, can induce cell death in MCF-7 cells. Together, our results identify the specificity and cellular targets of these novel inhibitors and suggest that SIRT inhibitors require combined targeting of both SIRT1 and SIRT2 to induce p53 acetylation and cell death. Mol Cancer Ther; 9(4); 844-55. ©2010 AACR.

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“…Ile347 and Ile348 were extensively residue domain to binding pocket for the ligand. 26 The results of the hydrogen bond analysis also show that residual Ile347 and Asp348 have high occupancy that plays a role in inhibitor activity. Based on research results the 5-oxocoronaridine and dregamine compounds are potential candidates for SIRT1 inhibitors.…”

Section: Resultsmentioning

confidence: 93%

Molecular Dynamics Simulation of SIRT1 Inhibitor from Indonesian Herbal Database

Andika¹,

Erlina²,

Azminah³

et al. 2018

JYP

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Objective: Sirtuins are protein deacetylases regulating cellular metabolism, lifespan, stress responses, and linked with diseases pathogenesis such as cancer and neurodegenerative diseases. SIRT1, one of human seven sirtuins, the most widely studied today. Hence, identification of SIRT1 drug compound has attracted in drug discovery community. To find good drug candidates could use in insilico methods as a quick tool for analyzing the biological activity of drugs virtually. Method: In silico methods in this research using molecular dynamics simulations that use Indonesia herbal database to identification hits compounds as the SIRT1 inhibitor. Analysis of molecular dynamics simulations in this study includes RMSD (root mean square deviation), RMSF (root mean square fluctuation), molecular mechanism Poisson-Boltzmann/surface area (MMPBSA) and hydrogen bonding. Results:The results showed that hits compounds, dregamine and 5-oxocoronaridine against two of macromolecules SIRT1 (PDB ID: 4I5I and 4ZZI) obtained free energy MMPBSA calculation about -23 kcal/mol Meanwhile occupancy hydrogen bonding of residues Ile347 and Asp348 about 80%. Conclusion: Hits compounds dregamine and 5-oxocoronaridine against two of macromolecules SIRT1 inhibitor (PDB ID: 4I5I and 4ZZI) obtained free energy MMPBSA calculation about -23 kcal/mol meanwhile occupancy hydrogen bonding of residues Ile347 and Asp348 about 80%. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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Comparative and pharmacophore model for deacetylase SIRT1

Cited by 47 publications

References 40 publications

Salermide, a Sirtuin inhibitor with a strong cancer-specific proapoptotic effect

Salermide, a Sirtuin inhibitor with a strong cancer-specific proapoptotic effect

SIRT Inhibitors Induce Cell Death and p53 Acetylation through Targeting Both SIRT1 and SIRT2

Molecular Dynamics Simulation of SIRT1 Inhibitor from Indonesian Herbal Database

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