SIRT2 enziminin aşırı ekspresyonunun birçok hastalık ile ilişkili olduğuna ve SIRT2 inhibisyonunun patolojilerin ilerlemesini geciktirdiğine dair çalışmaların varlığı, SIRT2 enzimine olan ilgiyi artırmıştır. Bu nedenle, SIRT2 inhibisyonu ciddi hastalıkların tedavisi için umut verici bir terapötik hedef haline gelmiştir. Bu çalışmada, daha önce bildirilen öncü bileşiğin köprü ve kuyruk grupları üzerinde yapısal modifikasyonlar yapılarak SIRT2 inhibisyon potansiyellerinin geliştirilmesi amaçlanmıştır. Sentezlenen bileşikler arasında ST49 (%50.07) ve ST60 (%54.03), SIRT1 ve SIRT3’e kıyasla SIRT2’ye karşı en iyi inhibisyonu sergilemişlerdir. Bu bileşiklerin öngörülen bağlanma konformasyonları, inhibitor etki için SIRT2 aktif bölgesindeki önemli etkileşimlerin varlığını desteklemiştir. Bu sonuçlar, gelecekteki tasarım çalışmaları için yol gösterici veriler sağlamaktadır.

The mammalian cytoplasmic protein SIRT2, a class III histone deacetylase family member, possesses NAD+-dependent lysine deacetylase/deacylase activity. Dysregulation of SIRT2 has been implicated in the pathogenesis of several diseases, including neurological and metabolic disorders and cancer; thus, SIRT2 emerges as a potential therapeutic target. Herein, we identified a series of diaryl acetamides (ST61-ST90) by the structural optimization of our hit STH2, followed by enhanced SIRT2 inhibitory potency and selectivity. Among them, ST72, ST85, and ST88 selectively inhibited SIRT2 with IC50 values of 9.97, 5.74, and 8.92 μM, respectively. Finally, the entire study was accompanied by in silico prediction of binding modes of docked compounds and the stability of SIRT2-ligand complexes. We hope our findings will provide substantial information for designing selective inhibitors of SIRT2.

In mammals, nicotinamide phosphoribosyltransferase (NAMPT) is a crucial enzyme in the nicotinamide adenine dinucleotide (NAD+) synthesis pathway catalyzing the condensation of nicotinamide (NAM) with 5-phosphoribosyl-1-pyrophosphate (PRPP) to produce nicotinamide mononucleotide (NMN). Given the pivotal role of NAD+ in a range of cellular functions, including DNA synthesis, redox reactions, cytokine generation, metabolism, and aging, NAMPT has become a promising target for many diseases, notably cancer. Therefore, various NAMPT inhibitors have been reported and classified as first and second-generation based on their chemical structures and design strategies, dual-targeted being one. However, most NAMPT inhibitors suffer from several limitations, such as dose-dependent toxicity and poor pharmacokinetic properties. Consequently, there is no clinically approved NAMPT inhibitor. Hence, research on discovering more effective and less toxic dual-targeted NAMPT inhibitors with desirable pharmacokinetic properties has drawn attention recently. This review summarizes the previously reported dual-targeted NAMPT inhibitors, focusing on their design strategies and advantages over the single-targeted therapies.

Through the utilization of fluorescence spectroscopy, electrochemical, and molecular docking methods, this research investigates the interaction between the antihistamine drug desloratadine and calf thymus double-stranded DNA (ct-dsDNA). Deoxyguanosine (dGuo) and deoxyadenosine (dAdo) oxidation signals were diminished by incubation with varying concentrations of desloratadine, as determined by differential pulse voltammetry (DPV). This change was ascribed to desloratadine's binding mechanism to ct-dsDNA. The binding constant (Kb) between desloratadine and ct-dsDNA was determined to be 2.2 × 105 M-1 throughout electrochemical experiments. In order to further develop our comprehension of the interaction mechanism between desloratadine and ct-dsDNA, a series of spectroscopic experiments and molecular docking simulations were conducted. The Kb value was found to be 8.85 × 104 M-1 at a temperature of 25 °C by the use of fluorescence spectroscopic techniques. In summary, the utilization of electrochemical and spectroscopic techniques, alongside molecular docking investigations, has led to the prediction that desloratadine has the capability to interact with ct-dsDNA by groove binding.

Sirtuin 2 (SIRT2) belongs to the family of silent information regulators (sirtuins), which comprises nicotinamide adenine dinucleotide (NAD+)-dependent protein lysine deacetylases. With a distribution across numerous tissues and organs of the human body, SIRT2 is involved in a wide range of physiological and pathological processes, such as regulating the cell cycle, energy metabolism, DNA repair, and tumorigenesis. Aberrant expression of SIRT2 has been closely associated with particular etiologies of human diseases, positioning SIRT2 as a promising therapeutic target. Herein, we detail the design overview and findings of novel symmetrical 2,7-disubstituted 9H-fluoren-9-one derivatives targeting SIRT2. SG3 displayed the most potent SIRT2-selective inhibitory profile, with an IC50 value of 1.95  μ M , and reduced the cell viability of human breast cancer MCF-7 cells accompanied by hyperacetylation of α-tubulin. Finally, molecular docking, molecular dynamics simulations, and binding free energy calculations using molecular mechanics/generalized born surface area method were performed to verify the binding ability of SG3 to SIRT2. Taken together, these results could enhance our understanding of the structural elements necessary for inhibiting SIRT2 and shed light on the mechanism of inhibition.

Background: The goal of the current study was to investigate the inhibitory activity of six phenolic compounds, i.e., rosmarinic acid, gallic acid, oleuropein, epigallocatechin gallate (EGCG), 3-hydroxytyrosol, and quercetin, against β-site amyloid precursor protein cleaving enzyme-1 (BACE1), also known as β-secretase or memapsin 2, which is implicated in the pathogenesis of Alzheimer’s disease (AD). Methods and Results: The inhibitory potential against BACE1, molecular docking simulations, as well as neurotoxicity and the effect on the AD-related gene expression of the selected phenolics were tested. BACE1 inhibitory activity was carried out using the ELISA microplate assay via fluorescence resonance energy transfer (FRET) technology. Molecular docking experiments were performed in the human BACE1 active site (PDB code: 2WJO). Neurotoxicity of the compounds was carried out in SH-SY5Y, a human neuroblastoma cell line, by the Alamar Blue method. A gene expression analysis of the compounds on fourteen genes linked to AD was conducted using the real-time polymerase chain reaction (RT-PCR) method. Rosmarinic acid, EGCG, oleuropein, and quercetin (also used as the reference) were able to inhibit BACE1 with their respective IC50 values 4.06 ± 0.68, 1.62 ± 0.12, 9.87 ± 1.01, and 3.16 ± 0.30 mM. The inhibitory compounds were observed to occupy the non-catalytic site of the BACE1. However, hydrogen bonds were found to be present between rosmarinic acid and EGCG and aspartic amino acid D228 in the catalytic site. Oleuropein and quercetin effectively suppressed the expression of PSEN, APOE, and CLU, which are recognized to be linked to the pathogenesis of AD. Conclusions: The outcomes of the work bring quercetin, EGCG, and rosmarinic acid to the forefront as promising BACE1 inhibitors.

Nicotinamide phosphoribosyltransferase (NAMPT) is an important regulator enzyme in the mammalian NAD+ synthesis pathway that catalyzes the condensation of nicotinamide (NAM) with 5-phosphoribosyl-1-pyrophosphate (PRPP) to produce nicotinamide mononucleotide (NMN). Considering NAD+ is involved in many cellular processes like cytokine production, metabolism, and aging, resulting in NAMPT has been regarded as a therapeutically important target for various diseases, particularly cancer. Hence, numerous NAMPT inhibitors have been reported to date. However, the side effect profile of these inhibitors have sparked interest in discovering new molecules. Herein, statistically validated field-based 3D-QSAR models were constructed using chemically diverse amide- and urea-containing NAMPT inhibitors. The contour maps resulting from the best model (R2 = 0.8412, Q2 = 0.8464, Pearson-r = 0.9270) were exploited to get insight into structural properties related to NAMPT inhibition and the outcomes of field-based 3D-QSAR analysis appear that the steric interactions contributed to the activity more than electrostatic, hydrophobic, hydrogen bond acceptor (HBA), hydrogen bond donor (HBD), and aromatic ring fields.

This study is designed to investigate the interaction of phenylpiperidine derivative drug paroxetine, which is an effective serotonin reuptake inhibitor and biomolecules through electrochemical, fluorescence spectroscopy, and molecular docking methods. The interaction between paroxetine and biomolecules was investigated by differ-ential pulse voltammetry according to the decrease in deoxyguanosine anodic oxidation signal of double -stranded calf thymus DNA. Fluorescence spectroscopy studies were performed by titrating paroxetine against double-stranded calf thymus DNA solution at four different temperatures. The fluorescent results showed that paroxetine had a great affinity to bind with double-stranded calf thymus DNA. Interaction studies demonstrate that paroxetine binds to double-stranded calf thymus DNA via intercalation binding mode, and the binding constant values were calculated as 7.24 x 104 M-1 and 1.52 x 104 M-1 at 25 degrees C, based on voltammetric and spectroscopic results, respectively. Moreover, with the aim of elucidating the interaction mechanism between paroxetine and double-stranded calf thymus DNA, electrochemical and fluorescence spectroscopy studies along with molecular docking analysis were made.

The absolute configurations of the known but unusual spiro-flavostilbenoids found in the bark of Yucca schidigera Roezl ex Ortgies, were determined by applying time-dependent density functional theory simulation of electronic circular dichroism spectra. The absolute configurations obtained were as follows: (2S,3R) for yuccaol A, yuccaol D and yuccalide A; (2S,3S) for yuccaol B, yuccaol C and yuccaol E; (2S,3S,2'S,3'S) for gloriosaol A; (2S,3R,2'S,3'R) for gloriosaol C; (2S,3S,2'S,3'R) for gloriosaol D; (2S,3R,2'S,3'S) for gloriosaol E. These findings indicate that the compounds are all biosynthetic derivatives either of (2R)-naringenin and trans-resveratrol or of trans-3,3',5,5'-tetrahydroxy-4'-methoxystilbene. In contrast, gloriosaols are direct derivatives of yuccaols (note that substituting by stilbenoid changes the absolute configuration of C-2 naringenin carbon to 2S). A putative mechanism for their biosynthesis is proposed taking into account key aspects of regio- and stereoselectivity. Yuccaol B and gloriosaol A showed in vitro moderate inhibitory effects against acetyl-/butyrylcholinesterases (AChE/BChE) with IC50 values of 43/81 and 45/65 μM respectively. The selectivity index values calculated from the IC50 values of BChE and AChE were 1.9 and 1.4. Molecular docking simulations showed their interaction with the peripheral anionic site of human AChE and the catalytic site of the human BChE.

Epigenetic modifications play an essential role in tumor suppression and promotion. Among the diverse range of epigenetic regulators, SIRT2, a member of NAD+-dependent protein deacetylates, has emerged as a crucial regulator of cellular processes, including cell cycle progression, DNA repair, and metabolism, impacting tumor growth and survival. In the present work, a series of N-(5-phenoxythiophen-2-yl)-2-(arylthio)acetamide derivatives were identified following a structural optimization of previously reported virtual screening hits, accompanied by enhanced SIRT2 inhibitory potency. Among the compounds, ST44 and ST45 selectively inhibited SIRT2 with IC50 values of 6.50 and 7.24 μM, respectively. The predicted binding modes of the two compounds revealed the success of the optimization run. Moreover, ST44 displayed antiproliferative effects on the MCF-7 human breast cancer cell line. Further, the contribution of SIRT2 inhibition in this effect of ST44 was supported by western blotting, affording an increased α-tubulin acetylation. Furthermore, molecular dynamics (MD) simulations and binding free energy calculations using molecular mechanics/generalized born surface area (MM-GBSA) method evaluated the accuracy of predicted binding poses and ligand affinities. The results revealed that ST44 exhibited a remarkable level of stability, with minimal deviations from its initial docking conformation. These findings represented a significant improvement over the virtual screening hits and may contribute substantially to our knowledge for further selective SIRT2 drug discovery.Communicated by Ramaswamy H. Sarma.

Sirtuin 2 (SIRT2) is involved in a wide range of processes, from transcription to metabolism to genome stability. Dysregulation of SIRT2 has been associated with the pathogenesis and progression of different diseases, such as cancer and neurodegenerative disorders. In this context, targeting SIRT2 activity by small molecule inhibitors is a promising therapeutic strategy for treating related conditions, particularly cancer. This review summarizes the regulatory roles and molecular mechanisms of SIRT2 in cancer and the attempts to evaluate potential antitumor activities of SIRT2-selective inhibitors by in vitro and in vivo testing, which are expected to deepen our understanding of the role of SIRT2 in tumorigenesis and progression and may offer important clues or inspiration ideas for developing SIRT2 inhibitors with excellent affinity and selectivity.

Tenofovir disoproxil is a nucleotide analog reverse-transcriptase inhibitor, which is a crucial enzyme in retroviruses such as human immunodeficiency virus (HIV). Tenofovir is used for the treatment of chronic hepatitis B and to prevent and treat HIV/AIDS. In this study, the interactions between BSA and DNA with drug were evaluated by using UV-vis spectrophotometry, spectrofluorometric and molecular docking experiments. UV-vis experiments showed hyperchromic effect, which means drug, and BSA/DNA interacted and lead to change in protein and double helix conformation. Fluorescence quenching mechanism for the interaction between BSA and tenofovir was static, quenching (Kq) and binding (Kb) constants were 9.9 x 103 M-1 and 3.16 x 104 M-1, respectively. Synchronous fluorescence quenching studies indicated microenvironment of tryptophan residue of BSA changed with the interaction. Competitive fluorescence studies with methylene blue (MB) and acridine orange (AO) were verified that tenofovir and DNA interaction was groove binding. Molecular docking was performed to investigate the possible binding mode of tenofovir and interactions with BSA and DNA, which resulted in site I of BSA and minor groove of DNA being the binding site for tenofovir.

Sirtuins (SIRTs) are described as NAD+-dependent deacetylases, also known as class III histone deacetylases. So far, seven sirtuin genes (SIRTS 1-7) have been identified and characterized in mammals and are also known to occur in bacteria and eukaryotes. SIRTs are involved in various biological processes, including endocrine system, apoptosis, aging and longevity, diabetes, rheumatoid arthritis, obesity, inflammation, etc. Among them, the best-characterized one is SIRT1. Small molecules seem to be the most effective SIRT modulators. Flavonoids have been reported to possess many positive effects favorable for human health, while relatively less research has been reported so far on their functions as SIRT modulation mechanisms. In this regard, we aimed to focus on the modulatory effects of flavonoids on SIRTs as the most common secondary metabolites in natural products. Our literature survey covering the years from 2006 to 2021 pointed out that flavonoids frequently interact with SIRT1 and SIRT3, followed by SIRT6. It can also be concluded that some popular flavonoid derivatives, eg., resveratrol, quercetin, and catechin derivatives, came forward in terms of SIRT modulation.

In this study, the interaction between the phosphodiesterase-3 enzyme inhibitor drug milrinone and biomolecules was investigated by electrochemical, fluorescence spectroscopy, and molecular docking studies for the first time. The interaction between milrinone and biomolecules was investigated according to the decrease in deoxyguanosine oxidation signals of milrinone and calf thymus double-stranded deoxyribonucleic acid (ct-dsDNA) by cyclic voltammetry and differential pulse voltammetry. In fluorescence spectroscopy studies, a competitive study was conducted on ct-dsDNA by adding a well-known fluorescent methylene blue and ct-dsDNA solution. The fluorescent results showed that milrinone had a higher affinity for ct-dsDNA binding compared to methylene blue. Interaction studies show that milrinone binds to ct-dsDNA via a groove-binding mode, and the binding constant values were calculated as 4.27 x 10(6) M-1 and 6.03 x 10(4) M-1 at 25 degrees C, based on cyclic voltammetry and spectroscopic results, respectively. As a result of the interaction of human serum albumin and milrinone, the binding coefficient was calculated as 4.11 x 10(6) M-1 by cyclic voltammetry. In addition, experimental results were confirmed by obtaining information about the possible spatial structure of the aggregate formed through theoretical calculations based on energy minimization for milrinone- ct-dsDNA and milrinone-human serum albumin mixtures with molecular insertion. (c) 2022 The Electrochemical Society ("ECS"). Published on behalf of ECS by IOP Publishing Limited.

Sirtuins (SIRTs) are described as NAD(+)-dependent deacetylases, also known as class III histone deacetylases. So far, seven sirtuin genes (SIRTS 1-7) have been identified and characterized in mammals and are also known to occur in bacteria and eukaryotes. SIRTs are involved in various biological processes, including endocrine system, apoptosis, aging and longevity, diabetes, rheumatoid arthritis, obesity, inflammation, etc. Among them, the best-characterized one is SIRT1. Small molecules seem to be the most effective SIRT modulators. Flavonoids have been reported to possess many positive effects favorable for human health, while relatively less research has been reported so far on their functions as SIRT modulation mechanisms. In this regard, we aimed to focus on the modulatory effects of flavonoids on SIRTs as the most common secondary metabolites in natural products. Our literature survey covering the years from 2006 to 2021 pointed out that flavonoids frequently interact with SIRT1 and SIRT3, followed by SIRT6. It can also be concluded that some popular flavonoid derivatives, e.g., resveratrol, quercetin, and catechin derivatives, came forward in terms of SIRT modulation.

Sirtuin 2 (SIRT2), member of sirtuin family, belongs to class III histone deacetylases (HDACs) and is majorly cytosolic with occasional nuclear translocation. The enzymatic activity of SIRT2 is dependent on nicotinamide adenine dinucleotide (NAD+) and SIRT2 regulates post-translational modifications that are responsible for deacetylation of lysine residues in histone and non-histone substrates. SIRT2, thus affects most likely multiple cellular processes, such as signaling, gene expression, aging, autophagy, and has been identified as potential drug target in relation to inflammation, neurodegenerative diseases and cancer. Therefore, probing potential selective inhibitors is essential for the accurate understanding of enzyme functions. Here, we report a series of heteroaryl2-carboxamide hybrids bearing substituted benzyl or substituted phenoxy group at the 5-position of the central heterocyclic ring. The synthesized compounds were screened against SIRT1-3 and MCF-7 human breast cancer cell line to evaluate their biological activity. The best SIRT2 inhibition profiles were displayed by ST29 (SIRT2 IC50 = 38.69 mu M) and ST30 (SIRT2 IC50 = 43.29 mu M) with excellent selectivity against SIRT2 over SIRT1 and SIRT3. Molecular docking study of the synthesized compounds into SIRT2 active site was performed to rationalize the remarkable SIRT2 inhibitory activity. Furthermore, we performed all-atom, explicit-solvent molecular dynamics (MD) simulations and end-point binding free energy calculations using molecular mechanics/generalized Born surface area (MM/GBSA) method to evaluate whether this design strategy was successfully deployed. The results implied that the binding poses and ligand affinities were predicted without significant loss of accuracy. Conclusively, the developed chemotypes were advocated as promising leads for SIRT2 inhibition and required further investigation for SIRT2-targeted drug discovery and development.

This study examines the interaction between pyrimidine nucleoside analogue azacytidine, an anti-leukemic drug, and DNA by employing electrochemical, UV-vis spectroscopy, fluorescence spectroscopy and molecular docking techniques. In the electrochemical technique, azacytidine and dsDNA interaction was investigated in two different ways: (1) in solution and (2) with a biosensor using differential pulse voltammetry (DPV) at a glassy carbon electrode. The interaction between azacytidine and dsDNA at increasing interaction times was investigated in line with the changes in adenine and guanine oxidation signals. In addition, interaction studies of polyguanine-azacytidine and polyadenine-azacytidine were performed with DPV. The binding constant values were calculated as 2.420 x 10(4) M-1 and 3.266 x 10(4) M-1 at 25 degrees C using UV and fluorescence spectroscopy, respectively. In conclusion, based on electrochemical and spectroscopic methods as well as molecular docking studies, it was predicted that azacytidine can bind to dsDNA via groove binding.

The binding of drugs to DNA plays a critical role in new drug discovery and is important for designing better drugs. In this study, the interaction and binding mode of calf-thymus double-stranded deoxyribonucleic acid (ct-dsDNA) with cinacalcet (CIN) from the calcimimetic drug that mimics the action of calcium on tissues group were investigated. The interaction of CIN with ct-dsDNA was observed by the differential pulse voltammetry (DPV) technique by following the decrease in electrochemical oxidation signals to deoxyguanosine and adenosine. A competitive study was performed on an indicator, methylene blue, to investigate the interaction of the drug with ct-dsDNA by fluorescence spectroscopy. Interaction studies have shown that the binding mode for the interaction of CIN with ct-dsDNA could be groove-binding. According to the results obtained, the binding constant values were found to be 6.30 × 104 M−1 and 3.16 × 105 M−1, respectively, at 25 °C as obtained from the cyclic voltammetry (CV) and spectroscopic techniques. Possible molecular interactions of CIN with dsDNA were explored via molecular docking experiments. The docked structure indicated that CIN could fit well into the minor groove of the DNA through H-bonding and π-π stacking contact with CIN.

Ethanolic extracts prepared from forty-seven macroalgae species collected from the Mediterranean Sea, Aegean Sea, and Sea of Marmara were tested at 200 mu g/mL against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and tyrosinase (TYR), crucial for insect vivacity. Only one alga extract, e.g. Dictyota dichotoma var. intricata (C.Agardh) Greville 1830, had a notable inhibition of BChE (72.0 +/- 0.07%), whereas the rest of the macroalgae possessed no or low inhibition of AChE (2.20 +/- 0.39% - 14.20 +/- 2.16%), BChE (0.62 +/- 0.07% - 41.20 +/- 3.07%), and TYR (< 10%). Several known diterpenes (isoamijiol, 14-deoxyamijiol, amijidictyol, dictyodial, and 4 alpha-acetoxydictyodial) found earlier in this species were proceeded to molecular docking experiments to figure out its interactions with BChE. Eleven of the 47 macroalgal extracts were selected based on sufficient availability for testing in larvicidal and adulticidal activity assays against female Aedes aegypti "Orlando1952" the mosquito vector of yellow fever and dengue. The selected extracts displayed a high adulticidal activity ranging between 80-100% activity at 5 mu g/mosquito. In contrast, only the ethanol extract of Ceramium siliquosumvar. elegans showed larvicidal mortality of 93.3 +/- 11.5% at 0.5 mu g/mL. Our findings show that the macroalgae and their metabolites could be sources of novel insecticidal agents. (C) 2021 SAAB. Published by Elsevier B.V. All rights reserved.

Some imidazopyridine-carboxamides and carboximidamides were synthesized and their cytotoxic activities were tested against human leukemia cell lines (K562 and HL-60), human colon cancer cell line (HCT-116), human multiple myeloma cell lines (U266 and H929) and normal mouse fibroblast cell line (L929) by MTT (Tetrazolium salt colorimetric assay). Among them, imidazopyridine-2-phenylcarboxamide analogues 21 a-23, gave the lowest IC50 value with the range of 5.9-9.8 mu M. Since the imidazopyridine ring exist in three tautomeric forms, N-alkylation with benzyl bromide under basic conditions (K2CO3, in DMF) formed the mixture of three regioisomers. Their structural assignments (16 a, 20 a, 16 b, 20 b-22 b and 16 c) were made with the use of two-dimensional H-1-H-1 NOE (Nuclear overhauser effect spectroscopy, NOESY) and H-1/C-13-N-15 HMBC (Heteronuclear Multiple Bond Correlation) experiments. We observed that, N-benzylation occurs at a higher ratio on the pyridine moiety as N-4-regiosomer. In order to analyze the possible interactions of compounds 21 a-23, which were found to display good cytotoxic effect against the cancer cell lines tested were selected to dock into Aurora A kinase (AURKA) active site. The results reported that the compounds occupied the ATP pocket via forming interactions with Lys141, Lys162, Thr217, and Tyr 219 indicating the binding affinity to the AURKA.