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The discovery of anti-retroviral (ARV) drugs over the past 36 years has introduced various classes, including nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitor, fusion, and integrase strand transfer inhibitors inhibitors. The introduction of combined highly active anti-retroviral therapies in 1996 was later proven to combat further ARV drug resistance along with enhancing human immunodeficiency virus (HIV) suppression. As though the development of ARV therapies was continuously expanding, the variation of action caused by ARV drugs, along with its current updates, was not comprehensively discussed, particularly for HIV-1 infection. Thus, a range of HIV-1 ARV medications is covered in this review, including new developments in ARV therapy based on the drug's mechanism of action, the challenges related to HIV-1, and the need for combination therapy. Optimistically, this article will consolidate the overall updates of HIV-1 ARV treatments and conclude the significance of HIV-1-related pharmacotherapy research to combat the global threat of HIV infection.
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Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Humanos , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta AtividadeRESUMO
Selenium nanoparticles (SeNPs) are an appealing carrier for the targeted delivery. The selenium nanoparticles are gaining global attention because of the potential therapeutic applications in several diseases e.g., rheumatoid arthritis (RA), inflammatory bowel disease (IBD), asthma, liver, and various autoimmune disorders like psoriasis, cancer, diabetes, and a variety of infectious diseases. Despite the fact still there is no recent literature that summarises the therapeutic applications of SeNPs. There are some challenges that need to be addressed like finding targets for SeNPs in various diseases, and the various functionalization techniques utilized to increase SeNP's stability while facilitating wide drug-loaded SeNP distribution to tumor areas and preventing off-target impacts need to focus on understanding more about the therapeutic aspects for better understanding the science behind it. Keeping that in mind we have focused on this gap and try to summarize all recent key targeted therapies for SeNPs in cancer treatment and the numerous functionalization strategies. We have also focused on recent advancements in SeNP functionalization methodologies and mechanisms for biomedical applications, particularly in anticancer, anti-inflammatory, and anti-infection therapeutics. Based on our observation we found that SeNPs could potentially be useful in suppressing viral epidemics, like the ongoing COVID-19 pandemic, in complement to their antibacterial and antiparasitic uses. SeNPs are significant nanoplatforms with numerous desirable properties for clinical translation.
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Nanopartículas , Selênio , Humanos , Selênio/uso terapêutico , Selênio/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Animais , COVID-19 , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , SARS-CoV-2/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodosRESUMO
Cytochrome P40 (CYP) enzymes dominate the metabolism of numerous endogenous and xenobiotic substances. While it is commonly believed that CYP-catalysed reactions result in the detoxication of foreign substances, these reactions can also yield reactive intermediates that can bind to cellular macromolecules to cause cytotoxicity or irreversibly inactivate CYPs that create them.Mechanism-based inactivation (MBI) produces either irreversible or quasi-irreversible inactivation and is commonly caused by CYP metabolic bioactivation to an electrophilic reactive intermediate. Many drugs that have been known to cause MBI in CYPs have been discovered as perpetrators in drug-drug interactions throughout the last 20-30 years.This review will highlight the key findings from the recent literature about the mechanisms of CYP enzyme inhibition, with a focus on the broad mechanistic elements of MBI for widely used drugs linked to the phenomenon. There will also be a brief discussion of the clinical or pharmacokinetic consequences of CYP inactivation with regard to drug interaction and toxicity risk.Gaining knowledge about the selective inactivation of CYPs by common therapeutic drugs helps with the assessment of factors that affect the systemic clearance of co-administered drugs and improves comprehension of anticipated interactions with other drugs or xenobiotics.
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Enzymes are biologically active complex protein molecules that catalyze most chemical reactions in living organisms, and their inhibitors accelerate biological processes. This review emphasizes medicinal food plants and their isolated chemicals inhibiting clinically important enzymes in common diseases. A mechanistic overview was investigated to explain the mechanism of these food bases enzyme inhibitors. The enzyme inhibition potential of medicinal food plants and their isolated substances was searched in Ovid, PubMed, Science Direct, Scopus, and Google Scholar. Cholinesterase, amylase, glucosidase, xanthine oxidase, tyrosinase, urease, lipoxygenase, and others were inhibited by crude extracts, solvent fractions, or isolated pure chemicals from medicinal food plants. Several natural compounds have shown tyrosinase inhibition potential, including quercetin, glabridin, phloretin-4-O-ß-D-glucopyranoside, lupinalbin, and others. Some of these compounds' inhibitory kinetics and molecular mechanisms are also discussed. Phenolics and flavonoids inhibit enzyme activity best among the secondary metabolites investigated. Several studies showed flavonoids' significant antioxidant and anti-inflammatory activities, highlighting their medicinal potential. Overall, many medicinal food plants, their crude extracts/fractions, and isolated compounds have been studied, and some promising compounds depending on the enzyme have been found. Still, more studies are recommended to derive potential pharmacologically active functional foods.
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Antiepileptic drugs are versatile drugs with the potential to be used in functional drug formulations with drug repurposing approaches. In the present review, we investigated the anticancer properties of antiepileptic drugs and interlinked cancer and epileptic pathways. Our focus was primarily on those drugs that have entered clinical trials with positive results and those that provided good results in preclinical studies. Many contributing factors make cancer therapy fail, like drug resistance, tumor heterogeneity, and cost; exploring all alternatives for efficient treatment is important. It is crucial to find new drug targets to find out new antitumor molecules from the already clinically validated and approved drugs utilizing drug repurposing methods. The advancements in genomics, proteomics, and other computational approaches speed up drug repurposing. This review summarizes the potential of antiepileptic drugs in different cancers and tumor progression in the brain. Valproic acid, oxcarbazepine, lacosamide, lamotrigine, and levetiracetam are the drugs that showed potential beneficial outcomes against different cancers. Antiepileptic drugs might be a good option for adjuvant cancer therapy, but there is a need to investigate further their efficacy in cancer therapy clinical trials.
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Anticonvulsivantes , Neoplasias , Neoplasias/tratamento farmacológico , Humanos , Anticonvulsivantes/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais , AnimaisRESUMO
BACKGROUND: The development of breast cancer (BC) and how it responds to treatment have both been linked to the involvement of inflammation. Chronic inflammation is critical in carcinogenesis, leading to elevated DNA damage, impaired DNA repair machinery, cell growth, apoptosis, angiogenesis, and invasion. Studies have found several targets that selectively modulate inflammation in cancer, limit BC's growth, and boost treatment effectiveness. Drug resistance and the absence of efficient therapeutics for metastatic and triple-negative BC contribute to the poor outlook of BC patients. SUMMARY: To treat BC, small-molecule inhibitors, phytomedicines, and nanoparticles are conjugated to attenuate BC signaling pathways. Due to their numerous target mechanisms and strong safety records, phytomedicines and nanomedicines have received much attention in studies examining their prospects as anti-BC agents by such unfulfilled demands. KEY MESSAGES: The processes involved in the affiliation across the progression of tumors and the spread of inflammation are highlighted in this review. Furthermore, we included many drugs now undergoing clinical trials that target cancer-mediated inflammatory pathways, cutting-edge nanotechnology-derived delivery systems, and a variety of phytomedicines that presently address BC.
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Antineoplásicos , Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Nanomedicina , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Inflamação/tratamento farmacológicoRESUMO
FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately 30% of acute myeloid leukemia (AML) patients. In the current study, the oxindole chemotype is employed as a structural motif for the design of new FLT3 inhibitors as potential hits for AML irradiation. Cell-based screening was performed with 18 oxindole derivatives and 5a-c inhibited 68%-73% and 83%-91% of internal tandem duplication (ITD)-mutated MV4-11 cell growth for 48- and 72-h treatments while only 0%-2% and 27%-39% in wild-type THP-1 cells. The most potent compound 5a inhibited MV4-11 cells with IC50 of 4.3 µM at 72 h while it was 8.7 µM in THP-1 cells, thus showing two-fold selective inhibition against the oncogenic ITD mutation. The ability of 5a to modulate cell death was examined. High-throughput protein profiling revealed low levels of the growth factors IGFBP-2 and -4 with the blockage of various apoptotic inhibitors such as Survivin. p21 with cellular stress mechanisms was characterized by increased expression of HSP proteins along with TNF-ß. Mechanistically, compounds 5a and 5b inhibited FLT3 kinase with IC50 values of 2.49 and 1.45 µM, respectively. Theoretical docking studies supported the compounds' ability to bind to the FLT3 ATP binding site with the formation of highly stable complexes as evidenced by molecular dynamics simulations. The designed compounds also provide suitable drug candidates with no violation of drug likeability rules.
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Antineoplásicos , Leucemia Mieloide Aguda , Oxindóis , Tirosina Quinase 3 Semelhante a fms , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Oxindóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Relação Estrutura-AtividadeRESUMO
The neuropathological substrate of dementia with Lewy bodies (DLB) is defined by the inextricable cross-seeding accretion of amyloid-ß (Aß) and α-synuclein (α-syn)-laden deposits in cholinergic neurons. The recent revelation that neuropeptide kisspeptin-10 (KP-10) is able to mitigate Aß toxicity via an extracellular binding mechanism may provide a new horizon for innovative drug design endeavors. Considering the sequence similarities between α-syn's non-amyloid-ß component (NAC) and Aß's C-terminus, we hypothesized that KP-10 would enhance cholinergic neuronal resistance against α-syn's deleterious consequences through preferential binding. Here, human cholinergic SH-SY5Y cells were transiently transformed to upsurge the mRNA expression of α-syn while α-syn-mediated cholinergic toxicity was quantified utilizing a standardized viability-based assay. Remarkably, the E46K mutant α-syn displayed elevated α-syn mRNA levels, which subsequently induced more cellular toxicity compared with the wild-type α-syn in choline acetyltransferase (ChAT)-positive cholinergic neurons. Treatment with a high concentration of KP-10 (10 µM) further decreased cholinergic cell viability, while low concentrations of KP-10 (0.01-1 µM) substantially suppressed wild-type and E46K mutant α-syn-mediated toxicity. Correlating with the in vitro observations are approximations from in silico algorithms, which inferred that KP-10 binds favorably to the C-terminal residues of wild-type and E46K mutant α-syn with CDOCKER energy scores of -118.049 kcal/mol and -114.869 kcal/mol, respectively. Over the course of 50 ns simulation time, explicit-solvent molecular dynamics conjointly revealed that the docked complexes were relatively stable despite small-scale fluctuations upon assembly. Taken together, our findings insinuate that KP-10 may serve as a novel therapeutic scaffold with far-reaching implications for the conceptualization of α-syn-based treatments.
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Kisspeptinas , alfa-Sinucleína , Peptídeos beta-Amiloides/metabolismo , Colinérgicos , Humanos , Kisspeptinas/genética , Kisspeptinas/farmacologia , RNA Mensageiro , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMO
Cancer is the leading cause of death and has remained a big challenge for the scientific community. Because of the growing concerns, new therapeutic regimens are highly demanded to decrease the global burden. Despite advancements in chemotherapy, drug resistance is still a major hurdle to successful treatment. The primary challenge should be identifying and developing appropriate therapeutics for cancer patients to improve their survival. Multiple pathways are dysregulated in cancers, including disturbance in cellular metabolism, cell cycle, apoptosis, or epigenetic alterations. Over the last two decades, natural products have been a major research interest due to their therapeutic potential in various ailments. Natural compounds seem to be an alternative option for cancer management. Natural substances derived from plants and marine sources have been shown to have anti-cancer activity in preclinical settings. They might be proved as a sword to kill cancerous cells. The present review attempted to consolidate the available information on natural compounds derived from plants and marine sources and their anti-cancer potential underlying EMT mechanisms.
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Produtos Biológicos , Neoplasias , Humanos , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Neoplasias/tratamento farmacológico , Apoptose , Ciclo CelularRESUMO
Hypertension is defined as the persistence of elevated blood pressure in the circulation system. The renin-angiotensin-aldosterone system is a major modulator of blood pressure. Among the risk factors of cardiovascular disease, hypertension is the most preventable and treatable, with drugs such as ACE inhibitors. Many ACE inhibitors are known to have undesirable side effects and hence, natural alternatives are being sought. Dietary polyphenols, particularly ellagitannins, are derived from plant products and are known to exhibit a variety of bioactivities. Geraniin, an ellagitannin has been shown to have antihypertensive activity in animal experiments. It is speculated that the metabolites of geraniin are responsible for its ACE inhibitory activity. We have performed in vitro ACE inhibition and in silico studies with geraniin and its metabolites (ellagic acid, urolithins). Our studies confirm that ellagic acid exhibited similar inhibitory potential to ACE as the positive control captopril.
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Inibidores da Enzima Conversora de Angiotensina/farmacologia , Carboxipeptidases/efeitos dos fármacos , Glucosídeos/metabolismo , Taninos Hidrolisáveis/metabolismo , Enzima de Conversão de Angiotensina 2 , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Simulação por Computador , Cumarínicos , Ácido Elágico/metabolismo , Ácido Elágico/farmacologia , Ácido Elágico/uso terapêutico , Humanos , Hipertensão/tratamento farmacológico , Simulação de Acoplamento Molecular , Peptidil Dipeptidase A/efeitos dos fármacos , Polifenóis/farmacologia , CoelhosRESUMO
The biological, chemical, and in silico properties of methanol and dichloromethane (DCM) extracts of Alhagi maurorum roots with respect to the antioxidant, enzyme inhibition, and phytochemical composition were evaluated. Total bioactive contents were determined spectrophotometrically, and the individual secondary metabolites composition was assessed via ultra-high-performance liquid chromatography mass spectrometry (UHPLC-MS) analysis. Antioxidant capacities were evaluated using a panoply of assays (2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) free radical scavenging, ferric reducing antioxidant power (FRAP), cupric reducing antioxidant power (CUPRAC), phosphomolybdenum total antioxidant capacity (TAC), and metal chelating activity (MCA)). The enzyme inhibition potential was studied against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-amylase, α-glucosidase, tyrosinase, urease and lipoxygenase (LOX) enzymes. The methanol extract was found to contain higher total phenolic (105.91 mg GAE/g extract) and flavonoid (2.27 mg RE/g extract) contents which can be correlated to its more substantial antioxidant potential as well as AChE, BChE, tyrosinase and α-glucosidase inhibition. However, the DCM extract was the most effective against α-amylase (1.86 mmol ACAE/g extract) enzyme inhibition. The UHPLC-MS analysis of methanol extract identified the tentative presence of a total of 18 secondary metabolites, including flavonoids, saponins, phenolic and terpenoid derivatives. Three compounds named emmotin A, luteolin 5,3'-dimethyl ether, and preferrugone were further investigated for their in silico molecular docking studies against the tested enzymes. The selected compounds were found to have higher binding interaction with AChE followed by BChE, α-glucosidase, α-amylase, and tyrosinase. The results of the present study have demonstrated A. mauroram to be considered as a lead source of natural antioxidant and enzyme inhibitor compounds.
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Simulação por Computador , Simulação de Acoplamento Molecular/métodos , Compostos Fitoquímicos/análise , Extratos Vegetais/análise , Raízes de Plantas , Plantas Medicinais , Cromatografia Líquida de Alta Pressão/métodos , Compostos Fitoquímicos/química , Extratos Vegetais/química , Espectrometria de Massas em Tandem/métodosRESUMO
Many dietary supplements are promoted to patients with osteoarthritis (OA) including the three naturally derived compounds, glucosamine, chondroitin and diacerein. Despite their wide spread use, research on interaction of these antiarthritic compounds with human hepatic cytochrome P450 (CYP) enzymes is limited. This study aimed to examine the modulatory effects of these compounds on CYP2C9, a major CYP isoform, using in vitro biochemical assay and in silico models. Utilizing valsartan hydroxylase assay as probe, all forms of glucosamine and chondroitin exhibited IC50 values beyond 1000 µM, indicating very weak potential in inhibiting CYP2C9. In silico docking postulated no interaction with CYP2C9 for chondroitin and weak bonding for glucosamine. On the other hand, diacerein exhibited mixed-type inhibition with IC50 value of 32.23 µM and Ki value of 30.80 µM, indicating moderately weak inhibition. Diacerein's main metabolite, rhein, demonstrated the same mode of inhibition as diacerein but stronger potency, with IC50 of 6.08 µM and Ki of 1.16 µM. The docking of both compounds acquired lower CDOCKER interaction energy values, with interactions dominated by hydrogen and hydrophobic bondings. The ranking with respect to inhibition potency for the investigated compounds was generally the same in both in vitro enzyme assay and in silico modeling with order of potency being diacerein/rhein > various glucosamine/chondroitin forms. In vitro-in vivo extrapolation of inhibition kinetics (using 1 + [I]/Ki ratio) demonstrated negligible potential of diacerein to cause interaction in vivo, whereas rhein was predicted to cause in vivo interaction, suggesting potential interaction risk with the CYP2C9 drug substrates.
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Anti-Inflamatórios/farmacologia , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Citocromo P-450 CYP2C9/metabolismo , Antraquinonas/farmacologia , Artrite/tratamento farmacológico , Condroitina/farmacologia , Citocromo P-450 CYP2C9/química , Interações Medicamentosas , Glucosamina/farmacologia , Simulação de Acoplamento Molecular , Sulfafenazol/farmacologia , Valsartana/farmacologiaRESUMO
Quinolone is a heterocyclic compound containing carbonyl at the C-2 or C-4 positions with nitrogen at the C-1 position. The scaffold was first identified for its antibacterial properties, and the derivatives were known to possess many pharmacological activities, including anticancer. In this review, the quinolin-2(H)-one and quinolin-4(H)-one derivatives were identified to inhibit several various proteins and enzymes involved in cancer cell growth, such as topoisomerase, microtubules, protein kinases, phosphoinositide 3-kinases (PI3K) and histone deacetylase (HDAC). Hybrids of quinolone with curcumin or chalcone, 2-phenylpyrroloquinolin-4-one and 4-quinolone derivatives have demonstrated strong potency against cancer cell lines. Additionally, quinolones have been explored as inhibitors of protein kinases, including EGFR and VEGFR. Therefore, this review aims to consolidate the medicinal chemistry of quinolone derivatives in the pipeline and discuss their similarities in terms of their pharmacokinetic profiles and potential target sites to provide an understanding of the structural requirements of anticancer quinolones.
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Antineoplásicos , Quinolonas , Quinolonas/química , Quinolonas/farmacologia , Quinolonas/síntese química , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Química Farmacêutica , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologiaRESUMO
Cobra venom cytotoxins (CTX) cause dermonecrosis in envenomed patients who suffered from limb amputations due to the limitation of serotherapy-based antivenoms. This study aimed to identify small molecule inhibitors against CTX. A structure-based high-throughput virtual screening (HTVS) was conducted based on a conserved CTX, using the Natural Product Activity and Species Source (NPASS) screening library. The hits were valerenic acid, 1-oxo-2H-isoquinoline-4-carboxylic acid, acenaphthene, and 5-bromopyrrole-2-carboxamide, which interacted with contemporary antivenom binding site A and functional loops I-III of CTX, respectively, in molecular docking studies. Furthermore, molecular dynamic simulations were performed along with analysis of ligand fitness through their pharmacophore and pharmacokinetics properties. The antagonist effects of these hits on CTX-induced cytotoxicity were examined in human keratinocytes (HaCaT). Despite having a low binding affinity (KD = 14.45 × 10-4 M), acenaphthene demonstrated a significant increase of cell viability at 6 h and 24 h in experimental envenomed HaCaT. It also demonstrated the highest neutralization potency against CTX with a median effective concentration (EC50) of 0.05 mL/mg. Acenaphthene interacted with the functional loop II, which is the crucial cytotoxic site of CTX. It has an aromatic ring as its primary pharmacophoric feature, commonly used for rational drug design. In conclusion, acenaphthene could be a promising lead compound as a small molecule inhibitor.Communicated by Ramaswamy H. Sarma.
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Breast cancer (BC) is among the most frequent malignancies women face around the globe. Nanotherapeutics are constantly evolving to overcome the limitations of conventional diagnostic and therapeutic approaches. Nanotechnology-based nanocarriers have a higher entrapment efficiency, low cytotoxicity, greater stability and improved half-life than conventional therapy. Nano-drug delivery systems have improved pharmacokinetics and pharmacodynamics parameters because of nanomeric size. Currently, various nano-formulations are in preclinical and clinical settings for breast cancer, like polymeric nanoparticles, micelles, nanobodies, magnetic nanoparticles, liposomes, niosomes, gold-nanoparticles, dendrimers and carbon-nanotubes. This review highlights the recent advancement in developing nano-drug delivery systems for BC treatment. This review will open the gateway to researchers to understand the current approaches to developing nano-formulation and improving problems associated with conventional therapy.
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Neoplasias da Mama , Nanopartículas , Nanotubos de Carbono , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Sistemas de Liberação de Fármacos por Nanopartículas , Lipossomos , NanotecnologiaRESUMO
Leading pathological markers of Alzheimer's disease (AD) include Acetylcholinesterase (AChE), Butyrylcholinesterase (BuChE), Amyloid beta (Aß) and reactive oxygen species (ROS). Indole derivatives were identified and optimized to improve the potency against AChE, BuChE, Aß and ROS. The lead molecule IND-30 was found to be selective for AChE (selectivity ratio: 22.92) in comparison to BuChE and showed maximum inhibition potential for human AChE (IC50: 4.16 ± 0.063 µM). IND-30 was found to be safe on the SH-SY5Y cell line until the dose of 30 mM. Further, molecule IND-30 was evaluated for its ability to inhibit AChE-induced Aß aggregation at 0.5, 10 and 20 µM doses. Approximately, 50% of AChE-induced Aß aggregation was inhibited by IND-30. Thus, IND-30 was found to be multitargeting for AD.
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Despite extensive studies revealing the potential of cholinium-based ionic liquids (ILs) in protein stabilization, the nature of interaction between ILs' constituents and protein residues is not well understood. In this work, we used a combined computational and experimental approach to investigate the structural stability of a peptide hormone, insulin aspart (IA), in ILs containing a choline cation [Ch]+ and either dihydrogen phosphate ([Dhp]-) or acetate ([Ace]-) as anions. Although IA remained stable in both 1 M [Ch][Dhp] and 1 M [Ch][Ace], [Dhp]- exhibited a much stronger stabilization effect than [Ace]-. Both the hydrophilic ILs intensely hydrated IA and increased the number of water molecules in IA's solvation shell. Undeterred by the increased number of water molecules, the native state of IA's hydrophobic core was maintained in the presence of ILs. Importantly, our results reveal the importance of IL concentration in the medium which was critical to maintain a steady population of ions in the microenvironment of IA and to counteract the denaturing effect of water molecules. Through molecular docking, we confirm that the anions exert the dominant effect on the structure of IA, while [Ch]+ have the secondary influence. The computational results were validated using spectroscopic analyses (ultra-violet, fluorescence, and circular dichroism) along with dynamic light scattering measurements. The extended stability of IA at 30 °C for 28 days in 1 M [Ch][Dhp] and [Ch][Ace] demonstrated in this study reveals the possibility of stabilizing IA using cholinium-based ILs.
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Líquidos Iônicos , Simulação de Acoplamento Molecular , Líquidos Iônicos/química , Insulina Aspart , Cátions , Ânions , Água/químicaRESUMO
In the present research, oleuropein (OLE) contents from two Saudi Arabian wild olive trees (Olea europaea L.) leaves (O1 and O2), were collected from two nearby geographical sites differing in altitudes, and were determined via UHPLC-MS analysis. Moreover, total bioactive contents, antioxidant, and cytotoxicity (against MCF-7 and MDA-MB-231 cells) potential were also evaluated. The sample (O2) was found to contain significantly (p < 0.05) higher OLE content (4.13 ± 1.0 mg/g DW) compared with the sample (O1) having OLE content (3.63 ± 1.1 mg/g DW). A similar trend was observed regarding total bioactive contents and antioxidant potential. However, both samples exhibited low cytotoxicity against tested cell lines. Furthermore, with hierarchical cluster analysis that compared the results of our samples (O1 and O2) to other samples reported in the literature, it was found that the variance in OLE content and biological activities from Al Baha region leaves had a resemblance to other reported superior cultivars.
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Antineoplásicos , Olea , Antioxidantes/química , Olea/química , Iridoides/química , Arábia Saudita , Glucosídeos Iridoides , Antineoplásicos/química , Extratos Vegetais/química , Folhas de Planta/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/análiseRESUMO
BACKGROUND: Genetic polymorphism of cytochrome P450 (CYP) contributes to variability in drug metabolism, clearance, and response. This study aimed to investigate the functional and molecular basis for altered ligand binding and catalysis in CYP2D6*14A and CYP2D6*14B, two unique alleles common in the Asian population. METHODS: CYP proteins expressed in Escherichia coli were studied using the substrate 3-cyano-7- ethoxycoumarin (CEC) and inhibitor probes (quinidine, fluoxetine, paroxetine, terbinafine) in the enzyme assay. Computer modelling was additionally used to create three-dimensional structures of the CYP2D6*14 variants. RESULTS: Kinetics data indicated significantly reduced intrinsic clearance in CYP2D6*14 variants, suggesting that P34S, G169R, R296C, and S486T substitutions worked cooperatively to alter the conformation of the active site that negatively impacted the deethylase activity of CYP2D6. For the inhibition studies, IC50 values decreased in quinidine, paroxetine, and terbinafine but increased in fluoxetine, suggesting a varied ligand-specific susceptibility to inhibition. Molecular docking further demonstrated the role of P34S and R296C in altering access channel dimensions, thereby affecting ligand access and binding and subsequently resulting in varied inhibition potencies. CONCLUSION: In summary, the differential selectivity of CYP2D6*14 variants for the ligands (substrate and inhibitor) was governed by the alteration of the active site and access channel architecture induced by the natural mutations found in the alleles.
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Citocromo P-450 CYP2D6 , Quinidina , Alelos , Catálise , Citocromo P-450 CYP2D6/genética , Sistema Enzimático do Citocromo P-450/genética , Fluoxetina/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Paroxetina/farmacologia , TerbinafinaRESUMO
Quinolone is a privileged scaffold in medicinal chemistry and 4-Quinolone-3-Carboxamides have been reported to harbor vast therapeutic potential. However, conversion of N-1 substituted 4-Quinolone 3-Carboxylate to its corresponding carbamates is highly restrictive. This motivated us to adopt a much simpler, scalable and efficient methodology for the synthesis of highly pure N-1 substituted 4- Quinolone-3-Carboxamides with excellent yields. Our adopted methodology not only provides a robust pathway for the convenient synthesis of N-1 substituted 4- Quinolone-3-Carboxamides which can then be explored for their therapeutic potential, this may also be adaptable for the derivatization of other such less reactive carboxylate species.