Pharmacophore modeling and virtual screening studies to identify novel selective SIRT2 inhibitors

Eren, Gökçen; Bruno, Agostino; Guntekin-Ergun, Sezen; Cetin-Atalay, Rengül; Ozgencil, Fikriye; Özkan, Yeşim; Gozelle, Mahmut; Kaya, Selen Gozde; Costantino, Gabriele

doi:10.1016/j.jmgm.2019.02.014

Cited by 20 publications

(17 citation statements)

References 69 publications

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“…Virtual screening, molecular docking and simulation studies have made a significant contribution to the discovery of novel sirtuin inhibitors (Padmanabhan et al, 2016;Eren et al, 2019). Based on previous studies, it is possible to design, synthesize and screen novel indole molecules that can potentially inhibit cofactor binding (Manjula et al, 2019).…”

Section: Name Of the Compound Structure Resolutionmentioning

confidence: 99%

SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases

2021

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Sirtuins are NAD+ dependent histone deacetylases (HDAC) that play a pivotal role in neuroprotection and cellular senescence. SIRT1-7 are different homologs from sirtuins. They play a prominent role in many aspects of physiology and regulate crucial proteins. Modulation of sirtuins can thus be utilized as a therapeutic target for metabolic disorders. Neurological diseases have distinct clinical manifestations but are mainly age-associated and due to loss of protein homeostasis. Sirtuins mediate several life extension pathways and brain functions that may allow therapeutic intervention for age-related diseases. There is compelling evidence to support the fact that SIRT1 and SIRT2 are shuttled between the nucleus and cytoplasm and perform context-dependent functions in neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). In this review, we highlight the regulation of SIRT1 and SIRT2 in various neurological diseases. This study explores the various modulators that regulate the activity of SIRT1 and SIRT2, which may further assist in the treatment of neurodegenerative disease. Moreover, we analyze the structure and function of various small molecules that have potential significance in modulating sirtuins, as well as the technologies that advance the targeted therapy of neurodegenerative disease.

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Section: Name Of the Compound Structure Resolutionmentioning

confidence: 99%

SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases

2021

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“…Numerous SIRT2 inhibitors have been reported recently ( Fig. 1), 24,[30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] some of which are commercially available (e.g., SirReal2, AGK-2, tenovin-6). However, all of these compounds are endowed with limitations such as lack of isozyme selectivity, lack of potency (revealed by limited ability to inhibit demyristoylase activity), and/or poor solubility.…”

Section: Introductionmentioning

confidence: 99%

Mechanism-based inhibitors of SIRT2: structure–activity relationship, X-ray structures, target engagement, regulation of α-tubulin acetylation and inhibition of breast cancer cell migration

Nielsen¹,

Rajabi

Kudo

et al. 2020

Preprint

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Sirtuin 2 (SIRT2) is a protein deacylase enzyme that has been reported to remove both acetyl groups and longer chain acyl groups from lysine residues in post-translationally modified proteins. It affects diverse biological functions in the cell and has been considered a drug target in relation to both neurodegenerative diseases and cancer. Therefore, access to good chemical tool compounds are essential for the continued investigation of the complex function of this enzyme. Here, we report a collection of probes that are potent, selective, stable in serum, water soluble, amenable to cell culture experiments, and inhibit both SIRT2 deacetylation and demyristoylation. Compared to the current landscape of SIRT2 inhibitors, this is a unique ensemble of features built into a single compound.We expect the developed chemotypes to find broad applications in the interrogation of SIRT2 functions in both healthy and diseased cells to provide a foundation for the development of new therapeutics in the future.

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“…16-18). 264 In 2008, Manfred Jung and co-workers rst reported chemically induced degradation of Sirtuin 2 by PROTAC based on conjugation SirReals and thalidomide (Fig. 19).…”

Section: The Development Of Protacsmentioning

confidence: 99%