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1.
Klin Lab Diagn ; 66(3): 139-146, 2021 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-33793112

RESUMEN

Analysis of long-term treatment results of 101 primary gastric cancer patients at various stages of the tumor process followed during 1 - 41 months (median - 6,4 months) from the onset of specific treatment are presented depending on the levels of soluble forms (s) of PD-1 receptor and its ligand PD-L1 in blood plasma. Overall survival assessed by Kaplan-Meyer analysis and with the help of Cox multiparametric regression model was applied as the criterion of prognostic value. It was found that at high (≥ 35 pg/ml) sPD-L1 levels in blood plasma, the overall survival of patients with gastric cancer was statistically significantly lower than at the marker's levels below 35 pg / ml (p <0.045): 1-year survival comprised 78 and 96%, 2-year - 52 and 78%; 3-year - 40 and 61% at high and low sPD-L1 respectively. Median survival of patients with high plasma sPD-L1 comprised 29 months, of those with low sPD-L1 was not achieved during the whole follow-up period. This trend was observed not only in the total group of stage I-IV gastric cancer patients, but also in patients at the early stages of the disease, though sPD-L1 did not show an independent prognostic value in multiparametric model. At the same time, the overall survival of patients with gastric cancer did not depend on the baseline levels sPD-1 in blood plasma. Thus, soluble ligand sPD-L1 can be considered as a potentially valuable factor for prognosis of gastric cancer patients' survival, and, probably, of anti-PD-1/PD-L1 treatment efficiency, but further studies and patients' monitoring are required to prove this statement.


Asunto(s)
Receptor de Muerte Celular Programada 1 , Neoplasias Gástricas , Biomarcadores de Tumor , Humanos , Ligandos , Plasma , Pronóstico
2.
Nat Commun ; 12(1): 1616, 2021 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-33712620

RESUMEN

The polyketide natural product reveromycin A (RM-A) exhibits antifungal, anticancer, anti-bone metastasis, anti-periodontitis and anti-osteoporosis activities by selectively inhibiting eukaryotic cytoplasmic isoleucyl-tRNA synthetase (IleRS). Herein, a co-crystal structure suggests that the RM-A molecule occupies the substrate tRNAIle binding site of Saccharomyces cerevisiae IleRS (ScIleRS), by partially mimicking the binding of tRNAIle. RM-A binding is facilitated by the copurified intermediate product isoleucyl-adenylate (Ile-AMP). The binding assays confirm that RM-A competes with tRNAIle while binding synergistically with L-isoleucine or intermediate analogue Ile-AMS to the aminoacylation pocket of ScIleRS. This study highlights that the vast tRNA binding site of the Rossmann-fold catalytic domain of class I aminoacyl-tRNA synthetases could be targeted by a small molecule. This finding will inform future rational drug design.


Asunto(s)
Sitios de Unión/efectos de los fármacos , Ligasas/química , Ligasas/efectos de los fármacos , Piranos/antagonistas & inhibidores , ARN de Transferencia/efectos de los fármacos , Compuestos de Espiro/antagonistas & inhibidores , Aminoacil-ARNt Sintetasas/química , Aminoacil-ARNt Sintetasas/efectos de los fármacos , Isoleucina , Isoleucina-ARNt Ligasa/química , Isoleucina-ARNt Ligasa/efectos de los fármacos , Ligandos , Modelos Moleculares , Osteoporosis/tratamiento farmacológico , ARN de Transferencia/química , Saccharomyces cerevisiae
3.
J Biomed Nanotechnol ; 17(2): 263-278, 2021 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-33785097

RESUMEN

Pancreatic cancer is highly lethal and has a poor prognosis. The most common alteration during the formation of pancreatic tumors is the activation of KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) oncogene. As a new therapeutic strategy, the C19 molecule ((2S)-N-(2,5-dichlorophenyl)-2-[(3,4-dimethoxyphenyl)-methylamine]propanamide) blocks the KRAS-membrane association in cancer cells. In addition, the chemokine receptor CXCR4 is overexpressed in pancreatic cancer. In this research, a new dendrimer-based nanoradiopharmaceutical (177Lu-DN(C19)-CXCR4L) encapsulating C19 and functionalized to target CXCR4 receptors is proposed as both, a targeted radiotherapy system (lutetium-177) and an oncotherapeutic approach by the stabilization of KRAS4b-PDESδ complex to produce dual-specific therapy in pancreatic cancer. 177The Lu-DN(C19)-CXCR4L was synthesized and characterized, C19 was encapsulated with 81% efficiency, the final nanosystem rendered a particle size of 67 nm and the specific uptake in pancreatic cell lines was demonstrated. The major cytotoxic effect was observed in the KRAS-dependent and radioresistant cell line Mia PaCa-2, which expresses a high density of CXCR4 receptors. The radiation dose of 3 Gy/Bq decreased viability to 7%, and this effect was attributed to the presence of C19. A synergistic effect (radio and chemotherapy) capable of reducing viability in pancreatic cancer cells through apoptotic mechanisms was demonstrated. Thus, 177Lu-DN(C19)-CXCR4L nanoradiopharmaceutical is efficacious in pancreatic cancer cell lines overexpressing the CXCR4 receptor.


Asunto(s)
Neoplasias Pancreáticas , Receptores CXCR4 , Línea Celular Tumoral , Humanos , Ligandos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Receptores CXCR4/genética , Transducción de Señal
4.
Nat Commun ; 12(1): 1792, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741926

RESUMEN

In both sickle cell disease and malaria, red blood cells (RBCs) are phagocytosed in the spleen, but receptor-ligand pairs mediating uptake have not been identified. Here, we report that patches of high mannose N-glycans (Man5-9GlcNAc2), expressed on diseased or oxidized RBC surfaces, bind the mannose receptor (CD206) on phagocytes to mediate clearance. We find that extravascular hemolysis in sickle cell disease correlates with high mannose glycan levels on RBCs. Furthermore, Plasmodium falciparum-infected RBCs expose surface mannose N-glycans, which occur at significantly higher levels on infected RBCs from sickle cell trait subjects compared to those lacking hemoglobin S. The glycans are associated with high molecular weight complexes and protease-resistant, lower molecular weight fragments containing spectrin. Recognition of surface N-linked high mannose glycans as a response to cellular stress is a molecular mechanism common to both the pathogenesis of sickle cell disease and resistance to severe malaria in sickle cell trait.


Asunto(s)
Anemia de Células Falciformes/metabolismo , Eritrocitos/metabolismo , Manosa/metabolismo , Fagocitos/metabolismo , Polisacáridos/metabolismo , Membrana Eritrocítica/metabolismo , Membrana Eritrocítica/parasitología , Eritrocitos/parasitología , Citometría de Flujo/métodos , Hemólisis , Humanos , Ligandos , Malaria Falciparum/metabolismo , Malaria Falciparum/parasitología , Glicoproteínas de Membrana/metabolismo , Fagocitosis , Plasmodium falciparum/fisiología , Unión Proteica , Receptores Inmunológicos/metabolismo
5.
Nat Commun ; 12(1): 1347, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33649331

RESUMEN

The human microbiome can produce metabolites that modulate insulin signaling. Type 2 diabetes patients have increased circulating concentrations of the microbially produced histidine metabolite, imidazole propionate (ImP) and administration of ImP in mice resulted in impaired glucose tolerance. Interestingly, the fecal microbiota of the patients had increased capacity to produce ImP, which is mediated by the bacterial enzyme urocanate reductase (UrdA). Here, we describe the X-ray structures of the ligand-binding domains of UrdA in four different states, representing the structural transitions along the catalytic reaction pathway of this unexplored enzyme linked to disease in humans. The structures in combination with functional data provide key insights into the mechanism of action of UrdA that open new possibilities for drug development strategies targeting type 2 diabetes.


Asunto(s)
Imidazoles/metabolismo , Oxidorreductasas/metabolismo , Shewanella/enzimología , Ácido Urocánico/metabolismo , Arginina/metabolismo , Dominio Catalítico , Flavina-Adenina Dinucleótido/metabolismo , Imidazoles/química , Cinética , Ligandos , Modelos Moleculares , Oxidorreductasas/química , Conformación Proteica , Dominios Proteicos , Especificidad por Sustrato , Termodinámica , Ácido Urocánico/química
6.
Zhonghua Nei Ke Za Zhi ; 60(3): 243-246, 2021 Mar 01.
Artículo en Chino | MEDLINE | ID: mdl-33663174

RESUMEN

To investigate the clinical significance of serum soluble programmed cell death ligand-1 (PD-L1) in adult patients with community-acquired pneumonia (CAP). A total of 44 CAP patients, 54 severe CAP patients and 30 healthy volunteers were recruited in this study. Serum soluble PD-L1 were detected. Univariate and multivariate regression analyses were used to assess the influence of multiple clinical variables on prognosis. Serum soluble PD-L1 level in severe CAP group was 98.20(57.94, 128.90) ng/L, which was significantly higher than that in the CAP group [59.32(33.55, 92.58) ng/L] and healthy controls [20.44(12.15, 36.20) ng/L] (all P<0.001). PD-L1 level was positively correlated with CRUB-65(r=0.481, P<0.001) and the pneumonia severity index (PSI) score (r=0.442, P<0.001). Univariate regression analysis showed that CURB-65 (HR=2.544, 95%CI 1.324-4.889, P=0.005), PSI score (HR=1.036, 95%CI 1.012-1.061, P=0.004), soluble PD-L1(HR=1.013, 95%CI 1.001-1.026, P=0.041) were risk factors of mortality during hospitalization. Multivariate regression analysis suggested that PSI score (HR=1.042, 95%CI 1.012-1.073, P=0.005), soluble PD-L1 (HR=1.011, 95%CI 1.002-1.071, P=0.020) were independent predictors for mortality risk in CAP patients. CAP patients with soluble PD-L1≥98.20 ng/L had a significantly lower survival rate than those with soluble PD-L1<98.20 ng/L (P=0.033). In conclusion, this study indicates that serum soluble PD-L1 level in CAP patients is correlated with the survival prognosis.


Asunto(s)
Antígeno B7-H1 , Neumonía , Adulto , Apoptosis , Humanos , Ligandos , Pronóstico
7.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652554

RESUMEN

The translocator protein (TSPO) is a 18kDa transmembrane protein, ubiquitously present in human mitochondria. It is overexpressed in tumor cells and at the sites of neuroinflammation, thus representing an important biomarker, as well as a promising drug target. In mammalian TSPO, there are cholesterol-binding motifs, as well as a binding cavity able to accommodate different chemical compounds. Given the lack of structural information for the human protein, we built a model of human (h) TSPO in the apo state and in complex with PK11195, a molecule routinely used in positron emission tomography (PET) for imaging of neuroinflammatory sites. To better understand the interactions of PK11195 and cholesterol with this pharmacologically relevant protein, we ran molecular dynamics simulations of the apo and holo proteins embedded in a model membrane. We found that: (i) PK11195 stabilizes hTSPO structural fold; (ii) PK11195 might enter in the binding site through transmembrane helices I and II of hTSPO; (iii) PK11195 reduces the frequency of cholesterol binding to the lower, N-terminal part of hTSPO in the inner membrane leaflet, while this impact is less pronounced for the upper, C-terminal part in the outer membrane leaflet, where the ligand binding site is located; (iv) very interestingly, cholesterol most frequently binds simultaneously to the so-called CRAC and CARC regions in TM V in the free form (residues L150-X-Y152-X(3)-R156 and R135-X(2)-Y138-X(2)-L141, respectively). However, when the protein is in complex with PK11195, cholesterol binds equally frequently to the CRAC-resembling motif that we observed in TM I (residues L17-X(2)-F20-X(3)-R24) and to CRAC in TM V. We expect that the CRAC-like motif in TM I will be of interest in future experimental investigations. Thus, our MD simulations provide insight into the structural features of hTSPO and the previously unknown interplay between PK11195 and cholesterol interactions with this pharmacologically relevant protein.


Asunto(s)
Colesterol/química , Isoquinolinas/química , Estructura Secundaria de Proteína , Receptores de GABA/ultraestructura , Sitios de Unión/genética , Transporte Biológico/genética , Humanos , Ligandos , Mitocondrias/genética , Mitocondrias/ultraestructura , Modelos Moleculares , Simulación de Dinámica Molecular , Unión Proteica/genética , Dominios Proteicos/genética , Pliegue de Proteína , Receptores de GABA/química
8.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652639

RESUMEN

Hepatitis C is affecting millions of people around the globe annually, which leads to death in very high numbers. After many years of research, hepatitis C virus (HCV) remains a serious threat to the human population and needs proper management. The in silico approach in the drug discovery process is an efficient method in identifying inhibitors for various diseases. In our study, the interaction between Epigallocatechin-3-gallate, a component of green tea, and envelope glycoprotein E2 of HCV is evaluated. Epigallocatechin-3-gallate is the most promising polyphenol approved through cell culture analysis that can inhibit the entry of HCV. Therefore, various in silico techniques have been employed to find out other potential inhibitors that can behave as EGCG. Thus, the homology modelling of E2 protein was performed. The potential lead molecules were predicted using ligand-based as well as structure-based virtual screening methods. The compounds obtained were then screened through PyRx. The drugs obtained were ranked based on their binding affinities. Furthermore, the docking of the topmost drugs was performed by AutoDock Vina, while its 2D interactions were plotted in LigPlot+. The lead compound mms02387687 (2-[[5-[(4-ethylphenoxy) methyl]-4-prop-2-enyl-1,2,4-triazol-3-yl] sulfanyl]-N-[3(trifluoromethyl) phenyl] acetamide) was ranked on top, and we believe it can serve as a drug against HCV in the future, owing to experimental validation.


Asunto(s)
Catequina/análogos & derivados , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Proteínas del Envoltorio Viral/genética , Antivirales/química , Antivirales/farmacología , Catequina/química , Catequina/farmacología , Hepacivirus/genética , Hepacivirus/patogenicidad , Hepatitis C/virología , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Polifenoles/química , Polifenoles/farmacología , Té/química , Proteínas del Envoltorio Viral/antagonistas & inhibidores , Internalización del Virus/efectos de los fármacos
9.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652868

RESUMEN

Three new 3D metal-organic porous frameworks based on Co(II) and 2,2'-bithiophen-5,5'-dicarboxylate (btdc2-) [Co3(btdc)3(bpy)2]·4DMF, 1; [Co3(btdc)3(pz)(dmf)2]·4DMF·1.5H2O, 2; [Co3(btdc)3(dmf)4]∙2DMF∙2H2O, 3 (bpy = 2,2'-bipyridyl, pz = pyrazine, dmf = N,N-dimethylformamide) were synthesized and structurally characterized. All compounds share the same trinuclear carboxylate building units {Co3(RCOO)6}, connected either by btdc2- ligands (1, 3) or by both btdc2- and pz bridging ligands (2). The permanent porosity of 1 was confirmed by N2, O2, CO, CO2, CH4 adsorption measurements at various temperatures (77 K, 273 K, 298 K), resulted in BET surface area 667 m2⋅g-1 and promising gas separation performance with selectivity factors up to 35.7 for CO2/N2, 45.4 for CO2/O2, 20.8 for CO2/CO, and 4.8 for CO2/CH4. The molar magnetic susceptibilities χp(T) were measured for 1 and 2 in the temperature range 1.77-330 K at magnetic fields up to 10 kOe. The room-temperature values of the effective magnetic moments for compounds 1 and 2 are µeff (300 K) ≈ 4.93 µB. The obtained results confirm the mainly paramagnetic nature of both compounds with some antiferromagnetic interactions at low-temperatures T < 20 K in 2 between the Co(II) cations separated by short pz linkers. Similar conclusions were also derived from the field-depending magnetization data of 1 and 2.


Asunto(s)
Cobalto/química , Estructuras Metalorgánicas/ultraestructura , Conformación Molecular , Compuestos Organometálicos/química , Adsorción/efectos de los fármacos , Cristalografía por Rayos X , Ligandos , Fenómenos Magnéticos , Estructuras Metalorgánicas/química , Porosidad , Propiedades de Superficie
10.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652992

RESUMEN

Substances that can modify the androgen receptor pathway in humans and animals are entering the environment and food chain with the proven ability to disrupt hormonal systems and leading to toxicity and adverse effects on reproduction, brain development, and prostate cancer, among others. State-of-the-art databases with experimental data of human, chimp, and rat effects by chemicals have been used to build machine-learning classifiers and regressors and to evaluate these on independent sets. Different featurizations, algorithms, and protein structures lead to different results, with deep neural networks (DNNs) on user-defined physicochemically relevant features developed for this work outperforming graph convolutional, random forest, and large featurizations. The results show that these user-provided structure-, ligand-, and statistically based features and specific DNNs provided the best results as determined by AUC (0.87), MCC (0.47), and other metrics and by their interpretability and chemical meaning of the descriptors/features. In addition, the same features in the DNN method performed better than in a multivariate logistic model: validation MCC = 0.468 and training MCC = 0.868 for the present work compared to evaluation set MCC = 0.2036 and training set MCC = 0.5364 for the multivariate logistic regression on the full, unbalanced set. Techniques of this type may improve AR and toxicity description and prediction, improving assessment and design of compounds. Source code and data are available on github.


Asunto(s)
Aprendizaje Profundo , Unión Proteica/genética , Proteínas/genética , Receptores Androgénicos/genética , Algoritmos , Animales , Humanos , Ligandos , Modelos Logísticos , Redes Neurales de la Computación , Ratas , Programas Informáticos
11.
Nat Commun ; 12(1): 1382, 2021 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-33654076

RESUMEN

Mechanistic understanding of oncogenic variants facilitates the development and optimization of treatment strategies. We recently identified in-frame, tandem duplication of EGFR exons 18 - 25, which causes EGFR Kinase Domain Duplication (EGFR-KDD). Here, we characterize the prevalence of ERBB family KDDs across multiple human cancers and evaluate the functional biochemistry of EGFR-KDD as it relates to pathogenesis and potential therapeutic intervention. We provide computational and experimental evidence that EGFR-KDD functions by forming asymmetric EGF-independent intra-molecular and EGF-dependent inter-molecular dimers. Time-resolved fluorescence microscopy and co-immunoprecipitation reveals EGFR-KDD can form ligand-dependent inter-molecular homo- and hetero-dimers/multimers. Furthermore, we show that inhibition of EGFR-KDD activity is maximally achieved by blocking both intra- and inter-molecular dimerization. Collectively, our findings define a previously unrecognized model of EGFR dimerization, providing important insights for the understanding of EGFR activation mechanisms and informing personalized treatment of patients with tumors harboring EGFR-KDD. Finally, we establish ERBB KDDs as recurrent oncogenic events in multiple cancers.


Asunto(s)
Receptores ErbB/química , Receptores ErbB/metabolismo , Duplicación de Gen , Terapia Molecular Dirigida , Oncogenes , Secuencia de Aminoácidos , Animales , Línea Celular , Proliferación Celular , Epítopos/metabolismo , Receptores ErbB/genética , Ligandos , Ratones , Neoplasias/metabolismo , Fosforilación , Unión Proteica , Dominios Proteicos , Multimerización de Proteína , Relación Estructura-Actividad
12.
Molecules ; 26(4)2021 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-33668468

RESUMEN

Nicotinamide-N-methyltransferase (NNMT) is a cytosolic enzyme catalyzing the transfer of a methyl group from S-adenosyl-methionine (SAM) to nicotinamide (Nam). It is expressed in many tissues including the liver, adipose tissue, and skeletal muscle. Its expression in several cancer cell lines has been widely discussed in the literature, and recent work established a link between NNMT expression and metabolic diseases. Here we describe our approach to identify potent small molecule inhibitors of NNMT featuring different binding modes as elucidated by X-ray crystallographic studies.


Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Enfermedades Metabólicas/tratamiento farmacológico , Enfermedades Metabólicas/enzimología , Nicotinamida N-Metiltransferasa/antagonistas & inhibidores , Animales , Sitios de Unión , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ensayos Analíticos de Alto Rendimiento , Humanos , Ligandos , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Modelos Moleculares , Niacinamida/metabolismo , Nicotinamida N-Metiltransferasa/metabolismo , Ratas , Especificidad por Sustrato/efectos de los fármacos
13.
J Vis Exp ; (168)2021 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-33682851

RESUMEN

Within the same patient, absence of NKG2D ligands (NKG2DL) surface expression was shown to distinguish leukemic subpopulations with stem cell properties (so called leukemic stem cells, LSCs) from more differentiated counterpart leukemic cells that lack disease initiation potential although they carry similar leukemia specific genetic mutations. NKG2DL are biochemically highly diverse MHC class I-like self-molecules. Healthy cells in homeostatic conditions generally do not express NKG2DL on the cell surface. Instead, expression of these ligands is induced upon exposure to cellular stress (e.g., oncogenic transformation or infectious stimuli) to trigger elimination of damaged cells via lysis through NKG2D-receptor-expressing immune cells such as natural killer (NK) cells. Interestingly, NKG2DL surface expression is selectively suppressed in LSC subpopulations, allowing these cells to evade NKG2D-mediated immune surveillance. Here, we present a side-by-side analysis of two different flow cytometry methods that allow the investigation of NKG2DL surface expression on cancer cells i.e., a method involving pan-ligand recognition and a method involving staining with multiple antibodies against single ligands. These methods can be used to separate viable NKG2DL negative cellular subpopulations with putative cancer stem cell properties from NKG2DL positive non-LSC.


Asunto(s)
Citometría de Flujo/métodos , Leucemia Mieloide Aguda/patología , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Anticuerpos Antineoplásicos/metabolismo , Biotinilación , Recuento de Células , Humanos , Ligandos , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Proteínas Recombinantes de Fusión/metabolismo , Coloración y Etiquetado , Células Tumorales Cultivadas
14.
Molecules ; 26(5)2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33668971

RESUMEN

WD40 is a ubiquitous domain presented in at least 361 human proteins and acts as scaffold to form protein complexes. Among them, WDR5 protein is an important mediator in several protein complexes to exert its functions in histone modification and chromatin remodeling. Therefore, it was considered as a promising epigenetic target involving in anti-cancer drug development. In view of the protein-protein interaction nature of WDR5, we initialized a campaign to discover new peptide-mimic inhibitors of WDR5. In current study, we utilized the phage display technique and screened with a disulfide-based cyclic peptide phage library. Five rounds of biopanning were performed and isolated clones were sequenced. By analyzing the sequences, total five peptides were synthesized for binding assay. The four peptides are shown to have the moderate binding affinity. Finally, the detailed binding interactions were revealed by solving a WDR5-peptide cocrystal structure.


Asunto(s)
Descubrimiento de Drogas , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Biblioteca de Péptidos , Péptidos Cíclicos/farmacología , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ligandos , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/química , Unión Proteica
15.
Molecules ; 26(4)2021 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-33669312

RESUMEN

Diabetes mellitus is a chronic disease and one of the fastest-growing health challenges of the last decades. Studies have shown that chronic low-grade inflammation and activation of the innate immune system are intimately involved in type 2 diabetes pathogenesis. Momordica charantia L. fruits are used in traditional medicine to manage diabetes. Herein, we report the purification of a new 23-O-ß-d-allopyranosyl-5ß,19-epoxycucurbitane-6,24-diene triterpene (charantoside XV, 6) along with 25ξ-isopropenylchole-5(6)-ene-3-O-ß-d-glucopyranoside (1), karaviloside VI (2), karaviloside VIII (3), momordicoside L (4), momordicoside A (5) and kuguaglycoside C (7) from an Indian cultivar of Momordica charantia. At 50 µM compounds, 2-6 differentially affected the expression of pro-inflammatory markers IL-6, TNF-α, and iNOS, and mitochondrial marker COX-2. Compounds tested for the inhibition of α-amylase and α-glucosidase enzymes at 0.87 mM and 1.33 mM, respectively. Compounds showed similar α-amylase inhibitory activity than acarbose (0.13 mM) of control (68.0-76.6%). Karaviloside VIII (56.5%) was the most active compound in the α-glucosidase assay, followed by karaviloside VI (40.3%), while momordicoside L (23.7%), A (33.5%), and charantoside XV (23.9%) were the least active compounds. To better understand the mode of binding of cucurbitane-triterpenes to these enzymes, in silico docking of the isolated compounds was evaluated with α-amylase and α-glucosidase.


Asunto(s)
Antiinflamatorios/farmacología , Simulación por Computador , Frutas/química , Glicósidos/química , Glicósidos/farmacología , Hipoglucemiantes/farmacología , Momordica charantia/química , Triterpenos/química , Triterpenos/farmacología , Animales , Antiinflamatorios/química , Bioensayo , Espectroscopía de Resonancia Magnética con Carbono-13 , Glicósidos/aislamiento & purificación , Hipoglucemiantes/química , Ligandos , Ratones , Conformación Molecular , Simulación del Acoplamiento Molecular , Espectroscopía de Protones por Resonancia Magnética , Células RAW 264.7 , ARN Mensajero/genética , ARN Mensajero/metabolismo , Triterpenos/aislamiento & purificación , alfa-Amilasas/química , alfa-Amilasas/metabolismo , alfa-Glucosidasas/química , alfa-Glucosidasas/metabolismo
16.
Molecules ; 26(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669746

RESUMEN

The new coordination polymers (CPs) [Zn(µ-1κO1:1κO2-L)(H2O)2]n·n(H2O) (1) and [Cd(µ4-1κO1O2:2κN:3,4κO3-L)(H2O)]n·n(H2O) (2) are reported, being prepared by the solvothermal reactions of 5-{(pyren-4-ylmethyl)amino}isophthalic acid (H2L) with Zn(NO3)2.6H2O or Cd(NO3)2.4H2O, respectively. They were synthesized in a basic ethanolic medium or a DMF:H2O mixture, respectively. These compounds were characterized by single-crystal X-ray diffraction, FTIR spectroscopy, thermogravimetric and elemental analysis. The single-crystal X-ray diffraction analysis revealed that compound 1 is a one dimensional linear coordination polymer, whereas 2 presents a two dimensional network. In both compounds, the coordinating ligand (L2-) is twisted due to the rotation of the pyrene ring around the CH2-NH bond. In compound 1, the Zn(II) metal ion has a tetrahedral geometry, whereas, in 2, the dinuclear [Cd2(COO)2] moiety acts as a secondary building unit and the Cd(II) ion possesses a distorted octahedral geometry. Recently, several CPs have been explored for the cyanosilylation reaction under conventional conditions, but microwave-assisted cyanosilylation of aldehydes catalyzed by CPs has not yet been well studied. Thus, we have tested the solvent-free microwave-assisted cyanosilylation reactions of different aldehydes, with trimethylsilyl cyanide, using our synthesized compounds, which behave as highly active heterogeneous catalysts. The coordination polymer 1 is more effective than 2, conceivably due to the higher Lewis acidity of the Zn(II) than the Cd(II) center and to a higher accessibility of the metal centers in the former framework. We have also checked the heterogeneity and recyclability of these coordination polymers, showing that they remain active at least after four recyclings.


Asunto(s)
Aldehídos/química , Cianuros/química , Microondas , Polímeros/química , Pirenos/química , Compuestos de Trimetilsililo/química , Catálisis , Enlace de Hidrógeno , Ligandos , Modelos Moleculares , Conformación Molecular , Polímeros/síntesis química , Solventes , Termogravimetría
17.
Molecules ; 26(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669881

RESUMEN

Ruta chalepensis L. (Rutaceae), a perennial herb with wild and cultivated habitats, is well known for its traditional uses as an anti-inflammatory, analgesic, antipyretic agent, and in the treatment of rheumatism, nerve diseases, neuralgia, dropsy, convulsions and mental disorders. The antimicrobial activities of the crude extracts from the fruits, leaves, stem and roots of R. chalepensis were initially evaluated against two Gram-positive and two Gram-negative bacterial strains and a strain of the fungus Candida albicans. Phytochemical investigation afforded 19 compounds, including alkaloids, coumarins, flavonoid glycosides, a cinnamic acid derivative and a long-chain alkane. These compounds were tested against a panel of methicillin-resistant Staphylococcus aureus (MRSA) strains, i.e., ATCC 25923, SA-1199B, XU212, MRSA-274819 and EMRSA-15. The MIC values of the active compounds, chalepin (9), chalepensin (10), rutamarin (11), rutin 3'-methyl ether (14), rutin 7,4'-dimethyl ether (15), 6-hydroxy-rutin 3',7-dimethyl ether (16) and arborinine (18) were in the range of 32-128 µg/mL against the tested MRSA strains. Compounds 10 and 16 were the most active compounds from R. chalepensis, and were active against four out of six tested MRSA strains, and in silico studies were performed on these compounds. The anti-MRSA activity of compound 16 was comparable to that of the positive control norfloxacin (MICs 32 vs 16 µg/mL, respectively) against the MRSA strain XU212, which is a Kuwaiti hospital isolate that possesses the TetK tetracycline efflux pump. This is the first report on the anti-MRSA property of compounds isolated from R. chalepensis and relevant in silico studies on the most active compounds.


Asunto(s)
Simulación por Computador , Furocumarinas/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Ruta/química , Ruta/crecimiento & desarrollo , Rutina/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Furocumarinas/química , Furocumarinas/aislamiento & purificación , Enlace de Hidrógeno , Irak , Ligandos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Rutina/química , Rutina/aislamiento & purificación
18.
Molecules ; 26(4)2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670371

RESUMEN

Metastasis is the major cause of death in colorectal cancer and it has been proven that inhibiting an interaction between adenomatous polyposis coli (APC) and Rho guanine nucleotide exchange factor 4 (Asef) efficaciously restrain metastasis. However, current inhibitors cannot achieve a satisfying effect in vivo and need to be optimized. In the present study, we applied molecular dynamics (MD) simulations and extensive analyses to apo and holo APC systems in order to reveal the inhibitor mechanism in detail and provide insights into optimization. MD simulations suggested that apo APC takes on a broad array of conformations and inhibitors stabilize conformation selectively. Representative structures in trajectories show specific APC-ligand interactions, explaining the different binding process. The stability and dynamic properties of systems elucidate the inherent factors of the conformation selection mechanism. Binding free energy analysis quantitatively confirms key interface residues and guide optimization. This study elucidates the conformation selection mechanism in APC-Asef inhibition and provides insights into peptide-based drug design.


Asunto(s)
Proteína de la Poliposis Adenomatosa del Colon/antagonistas & inhibidores , Neoplasias Colorrectales/tratamiento farmacológico , Péptidos/química , Proteína de la Poliposis Adenomatosa del Colon/química , Proteína de la Poliposis Adenomatosa del Colon/genética , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Ligandos , Simulación de Dinámica Molecular , Metástasis de la Neoplasia , Péptidos/antagonistas & inhibidores , Unión Proteica/efectos de los fármacos , Factores de Intercambio de Guanina Nucleótido Rho/antagonistas & inhibidores , Factores de Intercambio de Guanina Nucleótido Rho/química , Factores de Intercambio de Guanina Nucleótido Rho/genética
19.
Molecules ; 26(4)2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33670773

RESUMEN

Folate receptor alpha (FRα) is known as a biological marker for many cancers due to its overexpression in cancerous epithelial tissue. The folic acid (FA) binding affinity to the FRα active site provides a basis for designing more specific targets for FRα. Heterocyclic rings have been shown to interact with many receptors and are important to the metabolism and biological processes within the body. Nineteen FA analogs with substitution with various heterocyclic rings were designed to have higher affinity toward FRα. Molecular docking was used to study the binding affinity of designed analogs compared to FA, methotrexate (MTX), and pemetrexed (PTX). Out of 19 FA analogs, analogs with a tetrazole ring (FOL03) and benzothiophene ring (FOL08) showed the most negative binding energy and were able to interact with ASP81 and SER174 through hydrogen bonds and hydrophobic interactions with amino acids of the active site. Hence, 100 ns molecular dynamics (MD) simulations were carried out for FOL03, FOL08 compared to FA, MTX, and PTX. The root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of FOL03 and FOL08 showed an apparent convergence similar to that of FA, and both of them entered the binding pocket (active site) from the pteridine part, while the glutamic part was stuck at the FRα pocket entrance during the MD simulations. Molecular mechanics Poisson-Boltzmann surface accessible (MM-PBSA) and H-bond analysis revealed that FOL03 and FOL08 created more negative free binding and electrostatic energy compared to FA and PTX, and both formed stronger H-bond interactions with ASP81 than FA with excellent H-bond profiles that led them to become bound tightly in the pocket. In addition, pocket volume calculations showed that the volumes of active site for FOL03 and FOL08 inside the FRα pocket were smaller than the FA-FRα system, indicating strong interactions between the protein active site residues with these new FA analogs compared to FA during the MD simulations.


Asunto(s)
Simulación por Computador , Receptor 1 de Folato/química , Ácido Fólico/química , Compuestos Heterocíclicos/química , Sitios de Unión , Humanos , Enlace de Hidrógeno , Ligandos , Metotrexato/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Pemetrexed/química , Termodinámica
20.
Molecules ; 26(4)2021 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-33671247

RESUMEN

In the present study, naphthyl acetohydrazide (HL) ligand was prepared and used for the synthesis of new six amorphous transition metal (Co(II), Ni(II), Cu(II), Zn(II), Pb(II), Cd(II)) complexes. All the compounds were characterized by elemental analysis, UV-vis, FT-IR, 1H- and 13C-NMR, and Matrix-Assisted Laser Desorption Ionization (MALDI). The solubilization study was carried out by estimating the interaction between the metal complexes with surfactants viz. sodium stearate (SS) and Cetyltrimethylammonium bromide (CTAB). UV-Visible spectroscopy was employed to determine partitioning and binding parameters, whereas electrical conductivity measurements were employed to estimate critical micellar concentration (CMC), the extent of dissociation, and free energy of micellization. The CT-DNA interaction of synthesized compounds with DNA represents the major groove binding. The synthesized ligand and metal complexes were also tested against bacterial and fungal strains and it has been observed that Cu(II) complex is active against all the strains except Candida albicans, while Cd(II) complex is active against all bacterial and fungal strains except Pseudomonas. Among all compounds, only the Pd(II) complex shows reasonable activity against cervical cancer HeLa cell lines, representing 97% inhibition.


Asunto(s)
Antiinfecciosos/farmacología , Complejos de Coordinación/síntesis química , ADN/metabolismo , Hidrazonas/síntesis química , Hidrazonas/farmacología , Metales/química , Micelas , Neoplasias/patología , Bacterias/efectos de los fármacos , Espectroscopía de Resonancia Magnética con Carbono-13 , Supervivencia Celular/efectos de los fármacos , Conductividad Eléctrica , Células HeLa , Humanos , Hidrazonas/química , Ligandos , Pruebas de Sensibilidad Microbiana , Espectroscopía de Protones por Resonancia Magnética , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de Fourier , Tensoactivos/química
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