RESUMEN
Despite the tremendous progress that has occurred in recent years in cell biology and oncology, in chemical, physical and computer sciences, the disease cancer has continued as the major cause of death globally. Research organizations, academic institutions and pharmaceutical companies invest huge amounts of money in the discovery and development of new anticancer drugs. Though much effort is continuing and whatever available approaches are being attempted, the success of bringing one effective drug into the market has been uncertain. To overcome problems associated with drug discovery, several approaches are being attempted. One such approach has been the use of known, approved and marketed drugs to screen these for new indications, which have gained considerable interest. This approach is known in different terms as "drug repositioning or drug repurposing." Drug repositioning refers to the structure modification of the active molecule by synthesis, in vitro/ in vivo screening and in silico computational applications where macromolecular structure-based drug design (SBDD) is employed. In this perspective, we aimed to focus on the application of repositioning or repurposing of essential drug moieties present in drugs that are already used for the treatment of some diseases such as diabetes, human immunodeficiency virus (HIV) infection and inflammation as anticancer agents. This review thus covers the available literature where molecular modeling of drugs/enzyme inhibitors through SBDD is reported for antidiabetics, anti-HIV and inflammatory diseases, which are structurally modified and screened for anticancer activity using respective cell lines.
Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Reposicionamiento de Medicamentos , Descubrimiento de Drogas , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Diseño de FármacosRESUMEN
Fibroblast growth factor receptor (FGFR) plays a vital role in tissue regeneration, angiogenesis, and embryogenesis. 3D-QSAR and molecular modeling methods are widely used for designing novel compounds for the determination of inhibitory activity against the biological target. In the present study, 3D-QSAR (CoMFA and CoMSIA) analysis was performed on 1, 6-naphthyridines, and pyridopyrimidines as potential FGFR inhibitors as anticancer agents. The best CoMFA and CoMSIA models were generated from test and training set derivatives with leave-one-out correlation coefficients (q2) 0.591 and 0.667, cross-validated correlation coefficients (r2cv) 0.584 and 0.652, conventional coefficients (r2ncv) 0.978 and 0.975 respectively. The developed models were validated by a test set of 12 compounds providing acceptable predictive correlation coefficient (r2pred) 0.61 and 0.68 for both models. The generated CoMFA and CoMSIA contour maps could be used to design novel 1, 6-naphthyridine analogs. Molecular docking studies indicated that compound 75 occupied the active site of the FGFR kinase interacting with Glu520 in the catalytic region, Asp630 in the DFG motif, and Met524 in the hinge region which compared with standard drug Ponatinib. The molecular dynamics simulation analysis revealed that the inhibitor 75 displayed binding stability in the active site of the FGFR4 by making two hydrogen bonds and one π-cation interaction. Collectively the outcome of the study suggested that the applications of ligand-based and structure-based approaches could be applied for the design of new FGFR4 inhibitors as anticancer agents.Communicated by Ramaswamy H. Sarma.
Asunto(s)
Antineoplásicos , Relación Estructura-Actividad Cuantitativa , Simulación del Acoplamiento Molecular , Receptores de Factores de Crecimiento de Fibroblastos , Simulación de Dinámica Molecular , Antineoplásicos/farmacologíaRESUMEN
The conserved three-dimensional structure of receptor tyrosine kinases (RTKs) has been varyingly observed in prokaryotes to humans that actively participate in the phosphorylation process of tyrosine residues in the protein, which results in the alteration of protein's function. Mutation and transcriptional or post-translational modifications lead to a deregulation of kinases, which ultimately fallout into the development of pathological conditions like cancer. The human genome encodes two kinds of tyrosine kinases: non-receptor tyrosine kinases (NRTKs) and receptor tyrosine kinases (RTKs). Among these kinases, VEGF/VEGFR-2 signaling cascade is an important target to develop novel small-molecule inhibitors for the therapy of abnormal angiogenesis incorporated with cancer. Due to advances in the knowledge of the catalytic domain and 'DFG-motif' region, selective 'DFG-in' (type I) and 'DFG-out' (type II) VEGFR-2/KDR inhibitors were successfully developed, and some are in different phases of a clinical trial. 'DFG-out' (inactive) confirmation has significant advantages over 'DFG-in' (active) confirmation concerning the affinity of the ATP at the catalytic domain. Further, in the catalytic domain, between front and back cleft, smaller gatekeeper residue (Val916) present; therefore, selectivity against VEGFR-2 could be precisely achieved. In this review, small molecule type II/'DFG-out' inhibitors, their conformation, interaction at receptor binding pocket, and structural requirements to inhibit VEGFR-2 at the molecular level are discussed.HighlightsVEGFR-2 is a type of membrane-bound receptor tyrosine kinases (RTKs) that regulates the process of vasculogenesis and angiogenesis.Small molecule first-generation type I, 'DFG-in' and second-generation type II, 'DFG-out' VEGFR-2 inhibitors exhibit clinical benefits in the treatment of aberrant angiogenesis associated with cancer.Molecular docking of FDA approved and novel type II inhibitors were performed using X-ray crystal structures of VEGFR-2; binding site analysis was carried out.Structural requirements for the inhibition of VEGFR-2 were identified.
Asunto(s)
Inhibidores de Proteínas Quinasas , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Sitios de Unión , Humanos , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Tirosina , Receptor 2 de Factores de Crecimiento Endotelial Vascular/químicaRESUMEN
The epithelial-mesenchymal transition (EMT) is considered an essential process for cancer development and metastasis. Sorafenib, a RAF kinase and VEGFR-2 inhibitor, exhibits efficacy against advanced hepatocellular carcinoma (HCC), renal carcinoma, and thyroid cancer. It is well established that transforming growth factor-ß (TGF-ß) activated EMT is involved in the invasion and metastasis of Hep G2 cells in HCC. In this study, we investigated the effects of sorafenib on various biomarkers associated with EMT using flow cytometry. We found that sorafenib upregulated the epithelial marker E-cadherin and downregulated the mesenchymal marker vimentin. Furthermore, sorafenib downregulated the level of the EMT-inducing transcription factor SNAIL. Our findings provide insights into the mechanisms associated with the anti-EMT effects of VEGFR-2/RAF kinase inhibitors.
RESUMEN
Cancer stem cells (CSCs) are involved in recurrent hepatocellular carcinoma (HCC), yet there is a lack of effective treatment that targets these CSCs. CD44+ and CD133+ CSCs are markedly expressed in HepG2 cells and were isolated and characterized using fluorescence-activated cell sorting (FACS) analysis. Since piperine is known as an effective molecule against metastasis, we thought to investigate the effect of piperine against CD44+/CD133+ CSCs. Herein, piperine was found to be active against these CSCs. Also, it was found appropriate to respite at the 'subG0/G1 and G0/G1' phase of the cell cycle analysis, respectively. TGF-ß activated epithelial-mesenchymal transition (EMT) has been involved in the invasion and metastasis of HepG2 cells in hepatocellular carcinoma. Therefore, we next investigated the effect of piperine on different biomarkers that remarkably takes part in the process of EMT using flow cytometric analysis. Piperine was found able to repress the epithelial marker (E-cadherin) but was unable to restore the level of Vimentin (mesenchymal marker) and SNAIL (EMT-inducing transcription factor). Therefore, the findings of this study revealed that piperine could be an effective treatment strategy for recurrent hepatocarcinogenesis.
Asunto(s)
Alcaloides/farmacología , Antineoplásicos/farmacología , Benzodioxoles/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Alcaloides/síntesis química , Alcaloides/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Benzodioxoles/síntesis química , Benzodioxoles/química , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Simulación de Dinámica Molecular , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Alcamidas Poliinsaturadas/síntesis química , Alcamidas Poliinsaturadas/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Alzheimer's Disease is a complex progressive neurodegenerative disorder characterized by neurofibrillary tangles and senile plaques in various parts of the brain particularly cerebral cortex affecting memory and cognition. Nuclear receptors such as Peroxisome proliferator-activated receptor γ [PPAR-γ] is reported to have a role in lipid and glucose homeostasis in the brain, reduces the synthesis of Aß (beta-amyloid plaques) and also regulates mitochondrial biogenesis and inhibit the neuro-inflammation, which contributes for the improvement in the cognitive function in AD. Hence PPAR-γ is one of the newer targets for the researchers to understand the pathology of AD and to evolve the novel strategy to retard/reverse the progression of AD. PPAR-γ agonists such as Rosiglitazone and Pioglitazone have shown promising results in AD by decreasing neuro-inflammation and restoring glucose dysmetabolism leading to a reduction in neuronal deterioration. These agonists possess poor blood-brain permeability and are poor candidates for clinical use in AD. Therefore, search, design, and development for new PPAR- γ agonists with improved BBB penetration ability are imperative. The present work deals with the use of computational tools and techniques such as molecular docking, molecular dynamics to discover PPAR-γ agonists from the unexplored Seaweed Metabolite Database and predicts it's toxicological and physiochemical profile, thereby saving time and resources. Out of 1,110 seaweed compounds, the hit molecule BS052 displayed a strong binding affinity towards PPAR-γ, which possessed better lipid solubility indicating the potential to be considered as a PPAR-γ agonist, which may be useful in the management of AD.Communicated by Ramaswamy H. Sarma.
Asunto(s)
Enfermedad de Alzheimer , PPAR gamma/agonistas , Algas Marinas/química , Enfermedad de Alzheimer/tratamiento farmacológico , Humanos , Simulación del Acoplamiento MolecularRESUMEN
Hepatocellular carcinoma (HCC) is a malignancy characterized by neoangiogenesis, which is an augmented production of proangiogenic factors by the tumor and its adjacent infected cells. These dysregulated angiogenic factors are the therapeutic targets in anti-angiogenic drug development. The signaling pathway of vascular endothelial growth factor (VEGF)/VEGFR-2 is crucial for controlling the angiogenic responses in endothelial cells (ECs). In this study, we carried out a rational drug design approach wherein we have identified the novel orally bioavailable compound VS 8 as a potent VEGFR-2 inhibitor, which remarkably suppresses hVEGF and hVEGFR-2 expression in HUVECs and exhibits significant anti-angiogenic effects in CAM assay. Besides, VS 8 significantly induces apoptosis in HCC cell line (Hep G2). Later we examined its effectiveness against CD44+ and CD133+ CSCs. Here, VS 8 was found to be active against CSCs, and adequate for the cessation of the cell cycle at 'G0/G1' and 'S' phase in CD44+ and CD133+ CSCs respectively. Factually, transforming growth factor-ß (TGF-ß) stimulated epithelial-mesenchymal transition (EMT) induces invasion and migration of HCC cells, which results in the metastasis. Therefore, we studied the effect of VS 8 on EMT markers using flow cytometry, which suggested that VS 8 significantly upregulates E-cadherin (epithelial biomarker) and downregulates vimentin (mesenchymal biomarker). Further, VS 8 downregulates the expression of EMT-inducing transcription factors (EMT-TFs), i.e., SNAIL. Altogether, our findings indicate that VS 8 could be a promising drug candidate for cancer therapy.
Asunto(s)
Carcinoma Hepatocelular/patología , Diseño de Fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Hepáticas/patología , Células Madre Neoplásicas/efectos de los fármacos , Factor de Crecimiento Transformador beta/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Antígeno AC133/metabolismo , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Disponibilidad Biológica , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Receptores de Hialuranos/metabolismo , Ratones , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
A few fruits have short post-harvest life due to high metabolic activity, relatively high water content vulnerability towards microbes and loss of weight during their storage. Carboxymethyl cellulose (CMC)-Guar gum-silver nanocomposite films (CG-Ag0NC) are developed to address these issues. The silver nanoparticles were generated in the CMC-Guar gum matrix through a reduction by Mentha leaves extract. All the films were characterized by UV-vis spectroscopy, FT-IR, TGA, XRD, SEM, TEM, and zeta potential measurements. The antimicrobial activity of CG and CG-Ag0NC was measured by determining their zone inhibition values with ten food pathogenic microbes. The shelf life of CG-Ag0NC films was tested with the model fruit, strawberries, and compared with other packing films. The results are encouraging in terms of freshness, shelf-life and weight loss.
Asunto(s)
Antibacterianos/farmacología , Carboximetilcelulosa de Sodio/química , Galactanos/química , Mananos/química , Nanopartículas del Metal/química , Nanocompuestos/química , Gomas de Plantas/química , Plata/farmacología , Antibacterianos/química , Bacterias/efectos de los fármacos , Embalaje de Alimentos , Conservación de Alimentos , Fragaria , Mentha , Pruebas de Sensibilidad Microbiana , Plata/química , Resistencia a la TracciónRESUMEN
Polycrystalline Sr2SnO4 phosphors doped with Tb(3+) were prepared by conventional solid-state reaction method. Materials were characterized by powder XRD and EDS techniques. The luminescence properties of these materials were investigated under UV and VUV excitation. Upon excitation at 272 nm, phosphors exhibited intense emissions at 492 and 543 nm due to (5)D4 â (7)F6 and (5)D4 â (7)F5 transitions of Tb(3+) ions, respectively. Materials also exhibited strong emissions from these transitions under VUV excitation at 147, 173 and 230 nm. Quantitative analysis of the spectra indicated probable applications of these phosphors for PDP and other display devices as green emitting phosphors.
Asunto(s)
Luminiscencia , Sustancias Luminiscentes/química , Estroncio/química , Terbio/química , Compuestos de Estaño/química , Rayos Ultravioleta , Sustancias Luminiscentes/síntesis química , Mediciones Luminiscentes , Compuestos de Estaño/síntesis químicaRESUMEN
The luminescence properties of K(1/2)Bi(1/2)TiO(3):Pr(3+) and Na(1/2)Bi(1/2)TiO(3):Pr(3+) powders are investigated in the temperature range 10-600 K. The experimental data are interpreted on the basis of metal-to-metal charge transfer processes and by considering Bi(3+)-to-Pr(3+) sensitization effects.
RESUMEN
VMNS2e is a novel biphenyl compound, which in previous studies had showed most favourable interactions with the active site of protein tyrosine phosphatase 1B (PTP1B). The effect of acute and chronic treatment of VMNS2e (30mg/kg) was investigated in ob/ob mice. Plasma glucose was measured after acute administration of VMNS2e (30mg/kg) in both lean and ob/ob mice. In the chronic study, VMNS2e (30mg/kg) was given orally, once daily for 60days. Metformin (300mg/kg) was taken as standard therapy. Body weight, food intake and blood glucose was measured weekly while glycosylated hemoglobin A(1c) (HbA(1c)), insulin, triglyceride, total cholesterol, low density lipoprotein (LDL), fructosamine, non esterified fatty acid and organ weight were estimated after the completion of treatment period. Oral glucose tolerance test was performed on the last day of treatment. Liver and epididymal fat weights were taken. Acute dose of VMNS2e elicited an anti hyperglycemic effect. It reduced blood glucose by 14% (0.5h) and 35.6% (6h). Chronic VMNS2e treatment improved glucose tolerance by 25.3%. It decreased blood glucose levels. Hyperinsulinemia was reduced (19.6%). VMNS2e treatment had no significant effect on body weight and food consumption. VMNS2e treatment exhibited significant reduction (28.2%) in HbA(1c), plasma triglyceride (49%), LDL (24%) and fructosamine (13%) levels. VMNS2e treatment did not alter total cholesterol and non esterified fatty acid levels. Epididymal fat/body weight ratio was reduced (26.3%). VMNS2e exhibited both acute and chronic anti hyperglycemic effect, insulin sensitivity along with improvement in various lipid parameters and glycemic control.
Asunto(s)
Compuestos de Bifenilo/farmacología , Diabetes Mellitus/tratamiento farmacológico , Hipoglucemiantes/farmacología , Obesidad/tratamiento farmacológico , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Compuestos de Bifenilo/uso terapéutico , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patología , Diabetes Mellitus/fisiopatología , Ingestión de Alimentos/efectos de los fármacos , Epidídimo/citología , Epidídimo/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Hemoglobina Glucada/metabolismo , Hipoglucemiantes/uso terapéutico , Insulina/sangre , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Ratones , Obesidad/metabolismo , Obesidad/patología , Obesidad/fisiopatología , Tamaño de los Órganos/efectos de los fármacosRESUMEN
Phosphodiesterase-4 (PDE 4) enzyme has emerged as an invaluable target for the treatment of asthma, chronic obstructive pulmonary disease and rheumatoid arthritis. These findings have generated widespread interest in PDE-4 inhibitors as a potential molecular target for the development of new anti-inflammatory drugs. A series of N-substituted cis-tetra- and cis-hexahydrophthalazinone derivatives have been reported as novel, selective PDE-4 inhibitors with potent anti-inflammatory activity. In order to gain further insights into the structural requirements of novel series of N-substituted cis-tetra and cis-hexahydrophthalazinone derivatives as PDE-4 inhibitors, a three-dimensional quantitative structure activity relationship (3D-QSAR) was performed using Genetic Function Approximation (GFA). The QSAR model was generated using a training set of 45 molecules and the predictive ability of the resulting each model was assessed using a test set of 9 molecules. The internal and external consistency of final QSAR model was 0.675 and 0.750 respectively. Analysis of results from the present QSAR study indicates that shape and structural descriptors strongly govern the PDE-4 enzyme inhibitory activity. This QSAR study highlights the structural features required for PDE-4 enzyme inhibition and may be useful for design of potent PDE-4 inhibitors.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Inhibidores de Fosfodiesterasa 4/química , Inhibidores de Fosfodiesterasa 4/farmacología , Ftalazinas/farmacología , Relación Estructura-Actividad Cuantitativa , Antiinflamatorios no Esteroideos/química , Estructura Molecular , Ftalazinas/química , EstereoisomerismoRESUMEN
AIM: To study the effect of a new biphenyl synthetic compound showing interactions with the active site of protein tyrosine phosphatase 1B by docking and molecular dynamics, VMNS2e in streptozotocin-induced diabetic nephropathy in rats with various renal function parameters and renal ultrastructure. METHODS: Streptozotocin (55 mg/kg)-induced diabetic rats were orally treated once daily with VMNS2e (30, 60, and 120 mg/kg) for 8 weeks. The body weight and blood glucose levels of the rats were recorded during the study period. After 8 weeks of treatment creatinine clearance, urinary protein, blood urea nitrogen, urinary albumin excretion rate, and insulin levels were measured. An ultrastructure study of the kidney tissue was performed and the glomerular basement membrane thickness was measured. RESULTS: Eight weeks of VMNS2e treatment significantly reduced the fasting blood glucose level, attenuated elevating blood urea nitrogen levels, and reduced glomerular basement membrane thickness. CONCLUSION: It is concluded that VMNS2e treatment at 30 and 60 mg/kg, when given for 8 weeks, partly ameliorated early diabetic nephropathy in diabetic rats.
Asunto(s)
Compuestos de Bifenilo/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Albuminuria/tratamiento farmacológico , Animales , Compuestos de Bifenilo/química , Glucemia/efectos de los fármacos , Nitrógeno de la Urea Sanguínea , Peso Corporal , Dominio Catalítico/efectos de los fármacos , Creatinina/sangre , Creatinina/orina , Membrana Basal Glomerular , Hipoglucemiantes/química , Insulina/sangre , Riñón/efectos de los fármacos , Riñón/ultraestructura , Masculino , Proteinuria/tratamiento farmacológico , Ratas , Ratas Sprague-DawleyRESUMEN
Cyclooxygenase-2 (COX-2) inhibitors are widely used for the treatment of pain and inflammatory disorders such as rheumatoid arthritis and osteoarthritis. A series of novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives has been reported as COX-2 inhibitors. In order to understand the structural requirement of these COX-2 inhibitors, a ligand-based pharmacophore and atom-based 3D-QSAR model have been developed. A five-point pharmacophore with four hydrogen bond acceptors (A) and one hydrogen bond donor (D) was obtained. The pharmacophore hypothesis yielded a 3D-QSAR model with good partial least-square (PLS) statistics results. The training set correlation is characterized by PLS factors (r (2) = 0.642, SD = 0.65, F = 82.7, P = 7.617 e - 12). The test set correlation is characterized by PLS factors (Q (2) (ext) = 0.841, RMSE = 0.24,Pearson-R = 0.91). A docking study revealed the binding orientations of these inhibitors at active site amino acid residues (Arg513, Val523, Phe518, Ser530, Tyr355, His90) of COX-2 enzyme. The results of ligand-based pharmacophore hypothesis and atom-based 3D-QSAR give detailed structural insights as well as highlights important binding features of novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives as COX-2 inhibitors which can provide guidance for the rational design of novel potent COX-2 inhibitors.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Modelos Moleculares , Pirimidinas/química , Pirimidinas/farmacología , Relación Estructura-Actividad Cuantitativa , Sitios de Unión , Ciclooxigenasa 2/metabolismo , Humanos , Análisis de los Mínimos Cuadrados , LigandosRESUMEN
Indium borate and rare earth substituted indium borates (In(1-x)Ln(x)BO(3) (x=0.0 and 0.05; Ln=Gd, Eu, Dy and Sm)) are prepared at low temperature by metathesis reaction using InCl(3), LnCl(3) and NaBO(2). They are characterized by powder XRD and infrared spectroscopy. All the compositions (In(1-x)Ln(x)BO(3)) crystallize in hexagonal lattice with calcite structure. These borates gave characteristic IR vibrations of planar BO(3) group. Spin-Hamiltonian parameters for Gd(3+) are deduced from room temperature electron spin resonance spectrum of In(0.95)Gd(0.05)BO(3). The electron spin resonance spectrum of In(0.95)Gd(0.05)BO(3) gave several anisotropic lines with g>2.0. The ESR spectrum of the sample belongs to the "intermediate" category with 1/4Asunto(s)
Boratos/análisis
, Metales de Tierras Raras/análisis
, Frío
, Espectrofotometría Infrarroja
, Difracción de Rayos X
RESUMEN
Protein tyrosine phosphatase 1B (PTP 1B), a negative regulator of insulin receptor signaling system, has emerged as a highly validated, attractive target for the treatment of non-insulin dependent diabetes mellitus (NIDDM) and obesity. As a result there is a growing interest in the development of potent and specific inhibitors for this enzyme. This quantitative structure-activity relationship (QSAR) study for a series of formylchromone derivatives as PTP lB inhibitors was performed using genetic function approximation (GFA) technique. The QSAR models were developed using a training set of 29 compounds and the predictive ability of the QSAR model was evaluated against a test set of 7 compounds. The internal and external consistency of the final QSAR model was 0.766 and 0.785. The statistical quality of QSAR models was assessed by statistical parameters r2, r2 (crossvalidated r2), r2pred (predictive r2) and lack of fit (LOF) measure. The results indicate that PTP lB inhibitory activity of the formylchromone derivatives is strongly dependent on electronic, thermodynamic and shape related parameters.
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Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Química Farmacéutica/estadística & datos numéricos , Cromonas/química , Cromonas/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/enzimología , Humanos , Técnicas In Vitro , Modelos Químicos , Modelos Moleculares , Obesidad/tratamiento farmacológico , Obesidad/enzimología , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Relación Estructura-Actividad CuantitativaRESUMEN
The beneficial action of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with the inhibition of cyclooxygenase-2 (COX-2), whereas their harmful side effects are associated with the inhibition of COX-1. In order to understand a meaningful comparison of both classical NSAIDs and newer COX-2 drugs, a series of molecules from varied classes of COX-2 inhibitors was studied by the application of three-dimensional quantitative structure-activity relationships (3D-QSAR) using molecular descriptors obtained by genetic function approximation. The features responsible for the dual inhibition of COX-1 and COX-2 and the selective inhibition of COX-2 with factors contributing to the maintenance of optimum selectivity were identified. The QSAR models revealed the importance of thermodynamic, electronic, structural, and molecular shape analysis parameters, which can reasonably modulate the selectivity pattern to avoid unsolicited side effects. An improved understanding to rationalize the COX-1 and COX-2 binding profiles could be gained to develop safe drug design methods.
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Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/farmacología , Ciclooxigenasa 1/genética , Ciclooxigenasa 2/genética , Diseño de Fármacos , Concentración 50 Inhibidora , Estructura Molecular , Relación Estructura-Actividad CuantitativaRESUMEN
Bulk and nano sized pyrochlore of composition La(2-x)Gd(x)Zr(2)O(7) (x=0.025, 0.05, 0.075 and 0.1) have been prepared by sol-gel method. They are characterized by powder X-ray diffraction and infrared spectroscopy. The sintering temperature influences the particle size of the sample. The room temperature powder ESR of La(1.95)Gd(0.05)Zr(2)O(7) gave characteristic "U" spectrum. The influence of particle size on the ESR of Gd(3+) is investigated. Possible reason for the disappearance of "U" spectrum with increase in the particle size is given.
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Nanopartículas/química , Niobio/química , Tamaño de la Partícula , Espectroscopía de Resonancia por Spin del Electrón , Espectrofotometría Infrarroja , Difracción de Rayos XRESUMEN
A new class of 4'-methylbiphenyl-2-(substituted phenyl)carboxamide derivatives had been previously evaluated in vivo for their anti-inflammatory activities in animal models of inflammation. In the present study, the most active compound of that series, compound 4e (4'-methylbiphenyl-2-(4-carboxy phenyl)carboxamide), was investigated in detail for its anti-inflammatory, analgesic and ulcerogenic potential. Pretreatment of rats with 4e (100 mg/kg) reduced carrageenan induced rat paw edema at 3 h compared to control group. Dose dependent percent inhibition of granuloma formation, exudate volume, total leukocyte count was observed in 4e (25, 50 and 100 mg/kg) and celecoxib (CAS 169590-42-5; 5 mg/kg) treated groups in the cotton pellet granuloma and granuloma pouch technique, respectively, in rats. C-reactive proteins were absent in the 4e treated group. Compound 4e inhibited acetic acid induced writhing dose dependently (10, 20 and 30 mg/kg). Compound 4e was inactive in the hot plate test. Gastric toxicity screening experiments showed that compound 4e, both after single and repeated oral administration, is devoid of any gastric irritation in rats. The LD50 was found to be more than 2000 mg/kg.
Asunto(s)
Analgésicos/síntesis química , Analgésicos/farmacología , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Inflamación/tratamiento farmacológico , Ácido Acético , Analgésicos/toxicidad , Animales , Antiinflamatorios no Esteroideos/toxicidad , Compuestos de Bifenilo/toxicidad , Proteína C-Reactiva/metabolismo , Celecoxib , Femenino , Pie/patología , Mucosa Gástrica/patología , Granuloma/inducido químicamente , Granuloma/patología , Inflamación/inducido químicamente , Inflamación/patología , Masculino , Ratones , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Pirazoles/farmacología , Ratas , Ratas Wistar , Úlcera Gástrica/inducido químicamente , Sulfonamidas/farmacologíaRESUMEN
The histone deacetylase enzyme has increasingly become an attractive target for developing novel anticancer drugs. Hydroxamates are a new class of anticancer agents reported to act by selective inhibition of the histone deacetylase (HDAC) enzyme. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were employed to study three-dimensional quantitative structure-activity relationships (3D-QSARs). QSAR models were derived from a training set of 40 molecules. An external test set consisting of 17 molecules was used to validate the CoMFA and CoMSIA models. All molecules were superimposed on the template structure by atom-based, multifit and the SYBYL QSAR rigid body field fit alignments. The statistical quality of the QSAR models was assessed using the parameters r(2)(conv), r(2)(cv) and r(2)(pred). In addition to steric and electronic fields, ClogP was also taken as descriptor to account for lipophilicity. The resulting models exhibited a good conventional r(2)(conv) and cross-validated r(2)(cv) values up to 0.910 and 0.502 for CoMFA and 0.987 and 0.534 for CoMSIA. Robust cross-validation by 2 groups was performed 25 times to eliminate chance correlation. The CoMFA models exhibited good external predictivity as compared to that of CoMSIA models. These 3D-QSAR models are very useful for design of novel HDAC inhibitors.