RESUMO
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.
RESUMO
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.
Assuntos
Neoplasias , Sirtuína 2 , Humanos , Neoplasias/tratamento farmacológicoRESUMO
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.
Assuntos
Antineoplásicos , Inibidores Enzimáticos , Neoplasias , Nicotinamida Fosforribosiltransferase , Animais , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Estrutura Molecular , Neoplasias/tratamento farmacológico , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/metabolismo , Relação Estrutura-Atividade , NAD/química , NAD/metabolismo , Niacinamida/químicaRESUMO
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.
Assuntos
Acetamidas , Sirtuína 2 , Sirtuína 2/antagonistas & inibidores , Sirtuína 2/química , Sirtuína 2/metabolismo , Humanos , Acetamidas/química , Acetamidas/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/químicaRESUMO
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 heteroaryl-2-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 µM) and ST30 (SIRT2 IC50 = 43.29 µM) 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.
Assuntos
Inibidores de Histona Desacetilases , Sirtuína 2 , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Simulação de Acoplamento Molecular , Sirtuína 1/metabolismo , Relação Estrutura-Atividade , TiadiazóisRESUMO
Sirtuins (SIRTs) are a class of nicotinamide adenine dinucleotide (NAD+)-dependent protein histone deacetylases (HDACs) that are evolutionarily conserved from bacteria to mammals. This group of enzymes catalyses the reversible deacetylation of lysine residues in the histones or non-histone substrates using NAD+ as a cosubstrate. Numerous studies have demonstrated that the aberrant enzymatic activity of SIRTs has been linked to various diseases like diabetes, cancer, and neurodegenerative disorders. Previously, we performed a pharmacophore-based virtual screening campaign and an aryloxybenzamide derivative (1) displaying SIRT1/2 inhibitory effect was identified as a hit compound. In the current study, the hit-to-lead optimization on the hit compound was explored in order to improve the SIRT binding and inhibition. Fourteen compounds, ten of which were new, have been synthesized and subjected to in vitro biological evaluation for their inhibitory activity against SIRT1-3. By the structural modifications performed, a significant improvement was observed in selective SIRT1 inhibition for ST01, ST02, and ST11 compared to that of the hit compound. The highest SIRT2 inhibitory activity was observed for ST14, which was designed according to compatibility with pharmacophore model developed for SIRT2 inhibitors and thus, providing the interactions required with key residues in SIRT2 active site. Furthermore, ST01, ST02, ST11, and ST14 were subjected to in vitro cytotoxicity assay against MCF-7 human breast cancer cell line to determine the influence of the improvement in SIRT1/2 inhibition along with the structural modifications on the cytotoxic properties of the compounds. The cytotoxicity of the compounds was found to be correlated with their SIRT inhibitory profiles indicating the effects of SIRT1/2 inhibition on cancer cell viability. Overall, this study provides structural insights for further inhibitor improvement.
Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Sirtuína 1/antagonistas & inibidores , Sirtuína 2/antagonistas & inibidores , Sirtuína 3/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Benzamidas/síntese química , Benzamidas/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Sirtuína 1/metabolismo , Sirtuína 2/metabolismo , Sirtuína 3/metabolismo , Relação Estrutura-AtividadeRESUMO
Cholinesterase (ChE) inhibition is an important treatment strategy for Alzheimer's disease (AD) as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are involved in the pathology of AD. In the current work, ChE inhibitory potential of twenty-four natural products from different chemical classes (i.e., diosgenin, hecogenin, rockogenin, smilagenin, tigogenin, astrasieversianins II and X, astragalosides I, IV, and VI, cyclocanthosides E and G, macrophyllosaponins A-D, kokusaginin, lamiide, forsythoside B, verbascoside, alyssonoside, ipolamide, methyl rosmarinate, and luteolin-7-O-glucuronide) was examined using ELISA microtiter assay. Among them, only smilagenin and kokusaginine displayed inhibitory action against AChE (IC50 = 43.29 ± 1.38 and 70.24 ± 2.87 µg/mL, respectively). BChE was inhibited by only methyl rosmarinate and kokusaginine (IC50 = 41.46 ± 2.83 and 61.40 ± 3.67 µg/mL, respectively). IC50 values for galantamine as the reference drug were 1.33 ± 0.11 µg/mL for AChE and 52.31 ± 3.04 µg/mL for BChE. Molecular docking experiments showed that the orientation of smilagenin and kokusaginine was mainly driven by the interactions with the peripheral anionic site (PAS) comprising residues of hAChE, while kokusaginine and methyl rosmarinate were able to access deeper into the active gorge in hBChE. Our data indicate that similagenin, kokusaginine, and methyl rosmarinate could be hit compounds for designing novel anti-Alzheimer agents.
Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Sítios de Ligação , Produtos Biológicos/isolamento & purificação , Inibidores da Colinesterase/isolamento & purificação , Furanos/química , Furanos/farmacologia , Concentração Inibidora 50 , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Quinolinas/química , Quinolinas/farmacologia , Espirostanos/química , Espirostanos/farmacologia , Relação Estrutura-AtividadeRESUMO
Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the condensation of nicotinamide (NAM) with 5-phosphoribosyl-1-prophosphate (PRPP) to yield nicotinamide mononucleotide (NMN), a rate limiting enzyme in a mammalian salvage pathway of nicotinamide adenine dinucleotide (NAD+) synthesis. Recently, intracellular NAD+ has received substantial attention due to the recent discovery that several enzymes including poly(ADP-ribose) polymerases (PARPs), mono(ADP-ribose) transferases (ARTs), and sirtuins (SIRTs), use NAD+ as a substrate, suggesting that intracellular NAD+ level may regulate cytokine production, metabolism, and aging through these enzymes. NAMPT is found to be upregulated in various types of cancer, and given its importance in the NAD+ salvage pathway, NAMPT is considered as an attractive target for the development of new cancer therapies. In this study, the reported NAMPT inhibitors bearing amide, cyanoguanidine, and urea scaffolds were used to generate pharmacophore models and pharmacophore-based virtual screening studies were performed against ZINC database. Following the filtering steps, ten hits were identified and evaluated for their in vitro NAMPT inhibitory effects. Compounds GF4 (NAMPT IC50 = 2.15 ± 0.22 µM) and GF8 (NAMPT IC50 = 7.31 ± 1.59 µM) were identified as new urea-typed inhibitors of NAMPT which also displayed cytotoxic activities against human HepG2 hepatocellular carcinoma cell line with IC50 values of 15.20 ± 1.28 and 24.28 ± 6.74 µM, respectively.
Assuntos
Inibidores Enzimáticos/química , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Ureia/análogos & derivados , Sítios de Ligação , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Células Hep G2 , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Nicotinamida Fosforribosiltransferase/metabolismo , Relação Estrutura-Atividade , Ureia/metabolismo , Ureia/farmacologiaRESUMO
The present study investigated the capability of an essential oil mix (MO: 1% and 3%) in ameliorating amnesia and brain oxidative stress in a rat model of scopolamine (Sco) and tried to explore the underlying mechanism. The MO was administered by inhalation to rats once daily for 21 days, while Sco (0.7 mg/kg) treatment was delivered 30 min before behavioral tests. Donepezil (DP: 5 mg/kg) was used as a positive reference drug. The cognitive-enhancing effects of the MO in the Sco rat model were assessed in the Y-maze, radial arm maze (RAM), and novel object recognition (NOR) tests. As identified by gas chromatography-mass spectrometry (GC-MS), the chemical composition of the MO is comprised by limonene (91.11%), followed by γ-terpinene (2.02%), ß-myrcene (1.92%), ß-pinene (1.76%), α-pinene (1.01%), sabinene (0.67%), linalool (0.55%), cymene (0.53%), and valencene (0.43%). Molecular interactions of limonene as the major compound in MO with the active site of butyrylcholinesterase (BChE) was explored via molecular docking experiments, and Van der Waals (vdW) contacts were observed between limonene and the active site residues SER198, HIS438, LEU286, VAL288, and PHE329. The brain oxidative status and acetylcholinesterase (AChE) and BChE inhibitory activities were also determined. MO reversed Sco-induced memory deficits and brain oxidative stress, along with cholinesterase inhibitory effects, which is an important mechanism in the anti-amnesia effect. Our present findings suggest that MO ameliorated memory impairment induced by Sco via restoration of the cholinergic system activity and brain antioxidant status.
Assuntos
Amnésia/tratamento farmacológico , Antioxidantes/farmacologia , Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Óleos Voláteis/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Escopolamina/efeitos adversos , Acetilcolinesterase/metabolismo , Amnésia/induzido quimicamente , Animais , Escala de Avaliação Comportamental , Encéfalo/enzimologia , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Donepezila/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Concentração Inibidora 50 , Limoneno/farmacologia , Limoneno/uso terapêutico , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Simulação de Acoplamento Molecular , Óleos Voláteis/análise , Óleos Voláteis/uso terapêutico , Ratos , Ratos WistarRESUMO
In the current study, forty-four new [3-(2/3/4-methoxyphenyl)-6-oxopyridazin-1(6H)-yl]methyl carbamate derivatives were synthesized and evaluated for their ability to inhibit electric eel acetylcholinesterase (EeAChE) and equine butyrylcholinesterase (eqBuChE) enzymes. According to the inhibitory activity results, [3-(2-methoxyphenyl)-6-oxopyridazin-1(6H)-yl]methyl heptylcarbamate (16c, eqBuChE, IC50â¯=â¯12.8⯵M; EeAChE, no inhibition at 100⯵M) was the most potent eqBuChE inhibitor among the synthesized compounds and was found to be a moderate inhibitor compared to donepezil (eqBuChE, IC50â¯=â¯3.25⯵M; EeAChE, IC50â¯=â¯0.11⯵M). Kinetic and molecular docking studies indicated that compounds 16c and 14c (hexylcarbamate derivative, eqBuChE, IC50â¯=â¯35⯵M; EeAChE, no inhibition at 100⯵M) were mixed-type inhibitors which accommodated within the catalytic active site (CAS) and peripheral anionic site (PAS) of hBuChE through stable hydrogen bonding and π-π stacking. Furthermore, it was determined that [3-(2-methoxyphenyl)-6-oxopyridazin-1(6H)-yl]methyl (4-methylphenyl)carbamate 7c (eqBuChE, IC50â¯=â¯34.5⯵M; EeAChE, 38.9% inhibition at 100⯵M) was the most active derivative against EeAChE and a competitive inhibitor binding to the CAS of hBuChE. As a result, 6-(2-methoxyphenyl)pyridazin-3(2H)-one scaffold is important for the inhibitory activity and compounds 7c, 14c and 16c might be considered as promising lead candidates for the design and development of selective BuChE inhibitors for Alzheimer's disease treatment.
Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Piridazinas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Humanos , Modelos Moleculares , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/química , Relação Estrutura-AtividadeRESUMO
The ethyl acetate fraction of the methanolic extract of Yucca schidigera Roezl ex Ortgies bark exhibited moderate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity (IC50 47.44 and 47.40 µg mL-1, respectively). Gel filtration on Sephadex LH-20 and further RP-C18 preparative HPLC of EtOAc fraction afforded 15 known and 3 new compounds, stereoisomers of larixinol. The structures of the isolated spirobiflavonoids 15, 26, and 29 were elucidated using 1D and 2D NMR and MS spectroscopic techniques. The relative configuration of isolated compounds was assigned based on coupling constants and ROESY (rotating-frame Overhauser spectroscopy) correlations along with applying the DP4+ probability method in case of ambiguous chiral centers. Determination of absolute configuration was performed by comparing calculated electronic circular dichroism (ECD) spectra with experimental ones. Compounds 26 and 29, obtained in sufficient amounts, were evaluated for activities against AChE and BChE, and they showed a weak inhibition only towards AChE (IC50 294.18 µM for 26, and 655.18 µM for 29). Furthermore, molecular docking simulations were performed to investigate the possible binding modes of 26 and 29 with AChE.
Assuntos
Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Yucca/química , Cromatografia Líquida de Alta Pressão , Ativação Enzimática/efeitos dos fármacos , Flavonoides/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Compostos de Espiro/químicaRESUMO
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.
RESUMO
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.
Assuntos
Flavanonas , Yucca , Humanos , Simulação de Acoplamento Molecular , ResveratrolRESUMO
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 differential 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 ââwere calculated as 7.24 × 104 M-1 and 1.52 × 104 M-1 at 25 °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.
Assuntos
DNA , Paroxetina , Antidepressivos/farmacologia , Dicroísmo Circular , DNA/química , Simulação de Acoplamento Molecular , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , TermodinâmicaRESUMO
Pharmacological suppression of leukotriene biosynthesis by 5-lipoxygenase (5-LO)-activating protein (FLAP) inhibitors is a promising strategy to intervene with inflammatory, allergic and cardiovascular diseases. Virtual screening targeting FLAP based on a combined ligand- and structure-based pharmacophore model led to the identification of 1-(2-chlorobenzyl)-2-(1-(4-isobutylphenyl)ethyl)-1H-benzimidazole (7) as developable candidate. Compound 7 potently suppressed leukotriene formation in intact neutrophils (IC(50)=0.31 µM) but essentially failed to directly inhibit 5-LO suggesting that interaction with FLAP causes inhibition of leukotriene synthesis. For structural optimization, a series of 46 benzimidazole-based derivatives of 7 were synthesized leading to more potent analogues (70-72, 82) with IC(50)=0.12-0.19 µM in intact neutrophils. Together, our results disclose the benzimidazole scaffold bearing an ibuprofen fingerprint as a new chemotype for further development of anti-leukotriene agents.
Assuntos
Proteínas Ativadoras de 5-Lipoxigenase/metabolismo , Benzimidazóis/análise , Benzimidazóis/farmacologia , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/farmacologia , Leucotrienos/biossíntese , Benzimidazóis/síntese química , Benzimidazóis/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Flavonoides , Sirtuínas , Animais , Apoptose , Flavonoides/farmacologia , Humanos , Resveratrol , Sirtuínas/metabolismoRESUMO
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.
Assuntos
DNA , Cinacalcete , DNA/química , Simulação de Acoplamento Molecular , Oxirredução , Espectrometria de FluorescênciaRESUMO
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 × 104 M-1 and 3.266 × 104 M-1 at 25 °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.
Assuntos
Azacitidina , Técnicas Biossensoriais , Técnicas Biossensoriais/métodos , DNA/química , Técnicas Eletroquímicas/métodos , Eletrodos , Simulação de Acoplamento Molecular , Análise EspectralRESUMO
A series of monocationic new guanidinobenzimidazole derivatives were prepared in a four step process starting from 2-nitro-1,4-phenylendiamine. Their antiparasitic activity against Plasmodium falciparum, Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania donovani were evaluated in vitro. Two out of 20 tested monocationic compounds (7, 14) showed close activity with reference drug chloroquine against P. Falciparum. To understand the interactions between DNA minor groove and in vitro active compounds (7, 14) molecular docking studies were carried out. Stability and binding energies of DNA-ligand complexes formed by DNA with compounds 7 and 14 were measured by molecular dynamics simulations throughout 200 ns time. Root mean square deviation (RMSD) values of the ligands remained stable below 0.25 mm and root mean square fluctuation (RMSF) values of the active site residues with which it interacted decreased compared to the apo form. All compounds exhibited theoretical absorption, distribution, metabolism and excretion (ADME) profiles conforming to Lipinski's and Ghose's restrictive rules.
Assuntos
Antiprotozoários/farmacologia , Benzimidazóis/farmacologia , Guanidina/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/química , Benzimidazóis/síntese química , Benzimidazóis/química , Cátions/síntese química , Cátions/química , Cátions/farmacologia , Relação Dose-Resposta a Droga , Guanidina/síntese química , Guanidina/química , Leishmania donovani/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-Atividade , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacosRESUMO
Three novel series of diaryl heterocyclic derivatives bearing the 2-oxo-5H-furan, 2-oxo-3H-1,3-oxazole, and 1H-pyrazole moieties as the central heterocyclic ring were synthesized and their in vitro inhibitory activities on COX-1 and COX-2 isoforms were evaluated using a purified enzyme assay. The 2-oxo-5H-furan derivative 6b was identified as potent COX inhibitor with selectivity toward COX-1 (COX-1 IC(50)=0.061 microM and COX-2 IC(50)=0.325 microM; selectivity index (SI)=0.19). Among the 1H-pyrazole derivatives, 11b was found to be a potent COX-2 inhibitor, about 38 times more potent than Rofecoxib (COX-2 IC(50)=0.011 microM and 0.398 microM, respectively), but showed no selectivity for COX-2 isoform. Compound 11c demonstrated strong and selective COX-2 inhibitory activity (COX-1 IC(50)=1 microM, COX-2 IC(50)=0.011 microM; SI= approximately 92). Molecular docking studies of compounds 6b and 11b-d into the binding sites of COX-1 and COX-2 allowed to shed light on the binding mode of these novel COX inhibitors.