Virtual Screening in the Identification of Sirtuins’ Activity Modulators

Abstract

Sirtuins are NAD+-dependent deac(et)ylases with different subcellular localization. The sirtuins’ family is composed of seven members, named SIRT-1 to SIRT-7. Their substrates include histones and also an increasing number of different proteins. Sirtuins regulate a wide range of different processes, ranging from transcription to metabolism to genome stability. Thus, their dysregulation has been related to the pathogenesis of different diseases. In this review, we discussed the pharmacological approaches based on sirtuins’ modulators (both inhibitors and activators) that have been attempted in in vitro and/or in in vivo experimental settings, to highlight the therapeutic potential of targeting one/more specific sirtuin isoform(s) in cancer, neurodegenerative disorders and type 2 diabetes. Extensive research has already been performed to identify SIRT-1 and -2 modulators, while compounds targeting the other sirtuins have been less studied so far. Beside sections dedicated to each sirtuin, in the present review we also included sections dedicated to pan-sirtuins’ and to parasitic sirtuins’ modulators. A special focus is dedicated to the sirtuins’ modulators identified by the use of virtual screening.

Virtual Screening Combined with Enzymatic Assays to Guide the Discovery of Novel SIRT2 Inhibitors

“…In addition, SIRT2 inhibition is reported as beneficial in several nervous system disorders, such as Parkinson's Disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), depression, and ischemic stroke [14][15][16]. Recent data support the neuroprotective role played by SIRT2 inhibitors in cognitive impairment [17], suggesting that SIRT2 has a critical role in neurological diseases, being a potential therapeutic target for most of them [18].…”

Histone deacetylase functions and therapeutic implications for adult skeletal muscle metabolism

“…The need for developing more selective Sirtuins activators is still crucial. To this end, virtual screening has been used recently ( Abbotto et al, 2022 ). Long-term rigorous studies, with validated outcomes compared to placebo groups are needed in order to confirm the effectiveness and the safety of these different STACs on diabetes.…”

Discovery of Novel N-Acylhydrazone Derivatives as Potent Inhibitors of Sirtuin-1

“…25 Over the past years, different SIRT inhibitors have been found among various classes of compounds. 7,[26][27][28][29][30][31][32] Downregulating activity towards HDACs class III was identified in 2-anilinobenzamides (nicotinamide analogues), 33 some acetyl lysine mimics, 26 azomethines based on 2-hydroxy-1naphthaldehyde (sirtinol, JGB1714 and others analogues), 34,35 thioureas (cambinol, tenovin-6), 36,37 and thiobarbituric acid 5-ylidene derivatives, 38 bis(indolyl)maleinimides, 34 5-benzylidene-2-phenyl-1,3-dioxane-4,6-diones 39 and indole derivatives, 40,41 naphtho[2,1-b]pyrane-3ones (splitomicin and analogues), 42 thieno[3,2-d]pyrimidine-6-carboxamides, 43 2-substituted nicotinic acid ethyl esters, 44 dihydro-1,4-benzoxazine carboxamides, 45 1,5-dihydro-1H-pyrano[2,3-d]pyrimidine-2,4(3H)-diones, 46 dihydropyrano[2,3-c]pyrazole, 47 2-arylamino-3-cyanopyridines, 48 3-heteroarylmethylene isoindolin-1-ones, 49 1,8-dioxo-octahydroxanthenes, 50 highly ionized naphthylurea suramin, 51 and various substances from natural sources (amurensin G) 52 or modified natural products such as steroids. 35 Most of these compounds have been evaluated using enzymatic and cell-based assays.…”