As members of the Class III family of histone deacetylases (HDACs), sirtuins have a variety of critical biological functions, including the regulation of transcriptional repression, telomere maintenance, and DNA repair [1]. Up to now, a total of seven human sirtuin members (SIRT1-7) have been identified. Phylogenetic analysis, based on amino acid sequence, shows that sirtuins can be divided into four groups, among which SIRT6, present in the nucleus and endoplasmic reticulum, is classified as class IV and is known to have multiple enzymatic functions such as mono-ADP ribosylation, deacetylation, and acylation activities [2,3]. To control gene expression, telomere maintenance, and DNA repair, SIRT6 attaches to chromatin in the nucleus and is involved in the regulation of histones, transcription factors, and stress response proteins [[4], [5], [6]]. In addition, SIRT6 is also involved in regulating the secretion of tumor necrosis factor TNF-α in the endoplasmic reticulum [7]. Numerous studies have demonstrated that SIRT6 activation prevents metabolic and aging-related disorders, hence inhibiting it is considered a cancer treatment. Since SIRT6 has been associated with longevity, reduced inflammation, metabolic prevention, DNA repair, and involvement in the regulation of cancer, the protein has become an important target for new drug design and development [[8], [9], [10]].

Human SITR6 is 355 amino acids long and consists of a conserved catalytic domain at the N-terminus (1–296 amino acids) and a flanking tail at the C-terminus (297–355). Similar to other homologous sirtuins, all of them have a large Rossmann fold and zinc-binding domain-containing zinc ion-binding motifs. Between these two domains, SIRT6 forms a long hydrophobic cleft that is used to load substrate polypeptides and facilitate deacetylation reactions. SIRT6 has activities related to the regulation of many genes, and its histone 3 lysine 9 (H3K9) and histone 3 lysine 56 (H3K56) deacetylases, acylase and mono-ADP ribosylation activities have been identified [5,11,12]. Recent research shows that SIRT6 has a very weak deacetylase activity and a strong long-chain fatty acid acylase deacetylase activity [7]. SIRT6 was originally reported to be an autogenous ADP-ribosyl transferase: the transfer of NAD+ to SIRT6 by an intramolecular mechanism in which SIRT6 is able to undergo intramolecular auto-ADP-ribosylation using NAD+ as a co-substrate [13]. It has been shown that SIRT6 mono-ADP ribosylation ester PARP1 K521 has been shown to enhance double-strand breaks (DSBs) repair [14]. SIRT6 mono-ADP ribosylation BAF170 K312 promotes transcription of nuclear factor (erythroid-derived 2)-like 2 (NRF2) target genes [15]. Here, the mono-ADP ribosylation reaction (Fig. 1(A)) is a reaction in which ADP ribose is known to be transferred from NAD+ to the ε-amino group of lysine, ultimately producing nicotinamide and ADP-ribosyl protein. Studies have shown that sirtuins also bind zinc ions, which are essential for their deacetylase activity, but zinc ions are not directly involved in the deacetylase reaction, so zinc ions may help stabilize the conformation of the zinc-binding domain (ZBD) [16].

Quercetin (QUE) (Fig. 1(B)) is found in a variety of fruits and vegetables and is a polyphenolic flavonoid [17,18]. Some reports suggest that QUE has many pharmacological effects such as anti-inflammatory, antioxidant, anti-atherogenic, anticancer, antimicrobial, antidiabetic and anti-tumor activities [[19], [20], [21]]. Based on the " Fluor-de-Lys " (FdL) assay using fluorescent substrates, QUE has been proven to activate SIRT1 but inhibit SIRT6 [[22], [23]]. Based on mass spectrometry (MS) analysis, QUE has been further described as a SIRT6 inhibitor at low concentrations and a SIRT6 activator at high concentrations [24,25]. Recent studies have manifested that on the basis of a mass spectrometry study analysis, QUE is only a SIRT6 activator and that QUE inhibits other sirtuins isoforms by utilizing alternative binding sites [26,27].

Since the discovery of the deacetylase activity of SIRT6, a small number of activators and inhibitors have been reported, particularly some allosteric regulators such as MDL801 identified by drug screening [8,17,28]. In recent years, it has been demonstrated that QUE and its derivatives are weak SIRT6 modulators. These compounds have different degrees of influence on the catalytic effect of SIRT6 due to their different functional group structures, therefore, the design of novel SIRT6 modulators based on the structure of quercetin has become an important direction in the field of drug discovery. Computer research, as a modern scientific strategy, plays an important role in the study of the regulatory mechanism of quercetin and its derivatives on SIRT6. Through methods such as molecular modeling and molecular dynamics simulation, we can gain a more comprehensive and systematic understanding of the interaction mechanism between SIRT6 and quercetin and its derivatives, providing new ideas and methods for drug design and development. Although the binding site has now been revealed by molecular modeling studies [29], the regulatory mechanism of QUE on SIRT6 has not been fully understood. In the present research, quercetin-mediated SIRT6 substrate binding and interaction were investigated by molecular dynamics (MD) simulations to clarify the effects of QUE on the protein-substrate interaction in the SIRT6-mediated mono-ADP ribosylation [30].