RESUMEN
Interleukin-1 receptor associated kinase 3 (IRAK3) is a cytoplasmic homeostatic mediator of inflammatory responses and is potentially useful as a prognostic marker in inflammation. IRAK3 inhibits signalling cascades downstream of myddosome complexes associated with toll like receptors. IRAK3 contains a death domain that interacts with other IRAK family members, a pseudokinase domain and a C-terminus domain involved with tumour necrosis factor receptor associated factor 6 (TRAF6). Previous bioinformatic studies revealed that IRAK3 contained a guanylate cyclase centre in its pseudokinase domain but its role in IRAK3 action is unresolved. We demonstrate that wildtype IRAK3 is capable of producing cGMP. Furthermore, we show that a specific point mutation in the guanylate cyclase centre reduced cGMP production. Cells containing toll like receptor 4 and a nuclear factor kappa-light-chain-enhancer of activated B cells (NFĸB) reporter system were transfected with IRAK3 or mutant IRAK3 proteins. Cell-permeable cGMP treatment of untransfected control cells suppresses downstream signalling through modulation of the NFĸB in the presence of lipopolysaccharides. Cells transfected with wildtype IRAK3 also suppress lipopolysaccharide induced NFĸB activity in the absence of exogenous cGMP. Lipopolysaccharide induced NFĸB activity was not suppressed in cells transfected with the IRAK3 mutant with reduced cGMP-generating capacity. Whereas in the presence of exogenously applied cell-permeable cGMP the IRAK3 mutant was able to retain its function by suppressing lipopolysaccharide induced NFĸB activity. Furthermore, increasing the amount of membrane permeable cGMP did not affect IRAK3's ability to reduce NFĸB activity. These results suggest that cGMP generated by IRAK3 may be involved in regulatory function of the protein where the presence of cGMP may selectively affect downstream signalling pathway(s) by modulating binding and/or activity of nearby proteins that interact in the inflammatory signalling cascade.
Asunto(s)
Guanilato Ciclasa/metabolismo , Inmunidad Innata , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Transducción de Señal , Secuencia de Aminoácidos , Animales , Línea Celular , GMP Cíclico/metabolismo , Guanilato Ciclasa/química , Humanos , Quinasas Asociadas a Receptores de Interleucina-1/química , Quinasas Asociadas a Receptores de Interleucina-1/genética , Mutación Puntual , Homología de Secuencia de AminoácidoRESUMEN
Drug-likeness has long been studied in the pursuit of finding new medicines. Similarly, in the agrochemical field there is value in exploring the properties of the chemicals involved. Patterns that emerge can potentially influence future discovery campaigns to improve the probability of commercial success. In this study we investigate the acid/base properties and physicochemical characteristics of three classes of compounds: fungicides, herbicides and insecticides. In comparison with FDA-approved drugs, it was noted that the pesticides were generally smaller, possessed a neutral charge state and were more lipophilic. The results are discussed in the light of their intended targets.
Asunto(s)
Fungicidas Industriales/química , Herbicidas/química , Insecticidas/química , Relación Estructura-Actividad CuantitativaRESUMEN
Recent results using animal models of inflammatory skin conditions have shown that blockers of the voltage-gated potassium channel, Kv1.3 hold great promise for clinical utility. Kv1.3 blockers act as immunosuppressants by modulating the various subsets of inflammatory T and B cells involved in autoimmune disorders. While peptidic inhibitors based on naturally occurring venoms demonstrate potent and selective Kv1.3 blockade, these require parenteral administration and may face potential immunogenicity problems. Small molecule blockers show considerable diversity, however selectivity over other Kv1-family channels has been difficult to achieve. More recent advances have added to the evidence that Kv1.3 channels are a suitable therapeutic target and that the development of novel and selective agents will herald new drugs for inflammatory skin disorders.
Asunto(s)
Sistemas de Liberación de Medicamentos , Canal de Potasio Kv1.3/antagonistas & inhibidores , Bloqueadores de los Canales de Potasio/uso terapéutico , Psoriasis/tratamiento farmacológico , Humanos , Canal de Potasio Kv1.3/química , Bloqueadores de los Canales de Potasio/química , Psoriasis/inmunología , Psoriasis/fisiopatologíaRESUMEN
For the development of novel 5-HT(4) receptor ligands we have designed and synthesized two series of 5-methoxytryptamine derivatives varying the substitution on the primary amine. Their biological activities were evaluated in a receptor binding assay where a subset of compounds showed comparable potency to the agonists serotonin and 5-methoxytryptamine. Structure-activity analyses have highlighted promising avenues for further synthetic work and binding modes were proposed by docking these compounds into a homology model of the 5-HT(4) receptor.
Asunto(s)
Antagonistas del Receptor de Serotonina 5-HT4/síntesis química , Antagonistas del Receptor de Serotonina 5-HT4/farmacología , Triptaminas/farmacología , 5-Metoxitriptamina/análogos & derivados , 5-Metoxitriptamina/síntesis química , 5-Metoxitriptamina/metabolismo , 5-Metoxitriptamina/farmacología , Animales , Células COS , Chlorocebus aethiops , Diseño de Fármacos , Descubrimiento de Drogas , Humanos , Ligandos , Receptores de Serotonina 5-HT4/metabolismo , Receptores de Serotonina 5-HT4/fisiología , Triptaminas/agonistas , Triptaminas/síntesis química , Triptaminas/químicaRESUMEN
Acid-base ionization constant (pK(a)) values have considerable influence on the physicochemical and pharmacokinetic properties of therapeutic substances. A set of 907 drugs was examined to determine the proportion of drugs that contain an ionizable group and the distribution of their pK(a) values. Using this contemporary set of compounds it was found that 64% of these compounds contained an ionizable group. Within this group of ionizable compounds, 34% contained a single basic group while only 20% contained a single acidic functional group. The single acid and single base containing substances were investigated further to examine the distributions of their pK(a) values. These data are discussed and analyzed with a focus on the entire set as well as central nervous system, non-central nervous system and oral drugs. The findings from this research will prompt pharmaceutical companies to assess the constitution of their screening libraries, such that focus is placed on the proportion of ionizable substances, the ratio of acids to bases and the distribution of pK(a) values.
Asunto(s)
Descubrimiento de Drogas/métodos , Iones/química , Iones/farmacocinética , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Iones/metabolismo , CinéticaRESUMEN
A series of 30 tripeptides were synthesized and tested as novel 5-HT4 receptor ligands. Receptor binding assays showed that a subset of compounds had reasonable potency relative to the agonists serotonin and 5-methoxytryptamine. Structure-activity analyses and molecular docking have highlighted avenues for further synthetic work.
Asunto(s)
Descubrimiento de Drogas , Oligopéptidos/química , Oligopéptidos/metabolismo , Receptores de Serotonina 5-HT4/metabolismo , Secuencia de Aminoácidos , Aminas Biogénicas/metabolismo , Humanos , Ligandos , Modelos Moleculares , Receptores de Serotonina 5-HT4/químicaRESUMEN
Using a training set of 191 drug-like compounds extracted from the AQUASOL database a quantitative structure-property relationship (QSPR) study was conducted employing a set of simple structural and physicochemical properties to predict aqueous solubility. The resultant regression model comprised five parameters (ClogP, molecular weight, indicator variable for aliphatic amine groups, number of rotatable bonds and number of aromatic rings) and demonstrated acceptable statistics (r2 = 0.87, s = 0.51, F = 243.6, n = 191). The model was applied to two test sets consisting of a drug-like set of compounds (r2 = 0.80, s = 0.68, n = 174) and a set of agrochemicals (r2 = 0.88, s = 0.65, n = 200). Using the established general solubility equation (GSE) on the training and drug-like test set gave poorer results than the current study. The agrochemical test set was predicted with equal accuracy using the GSE and the QSPR equation. The results of this study suggest that increasing molecular size, rigidity and lipophilicity decrease solubility whereas increasing conformational flexibility and the presence of a non-conjugated amine group increase the solubility of drug-like compounds. Indeed, the proposed structural parameters make physical sense and provide simple guidelines for modifying solubility during lead optimisation.
Asunto(s)
Preparaciones Farmacéuticas/química , Modelos Moleculares , Modelos Estructurales , Relación Estructura-Actividad Cuantitativa , Análisis de Regresión , Reproducibilidad de los Resultados , SolubilidadRESUMEN
Platensimycin was recently discovered by Merck Research Laboratories and has created considerable interest given its potent antibacterial activity and mode of action. The use of RNA gene-silencing techniques and screening libraries of natural products allowed Merck to find this antibiotic which may have otherwise been missed using conventional methods. Interestingly, platensimycin has shown good activity against a panel of Gram positive organisms which included various resistant strains. Platensimycin works by inhibiting beta-ketoacyl synthases I/II (FabF/B) which are key enzymes in the production of fatty acids required for bacterial cell membranes. So far, a number of groups have explored synthetic strategies for platensimycin and this work has subsequently lead to the synthesis of active analogues. Given its mode of action, it is intriguing as to why Merck themselves patented only a single compound and have not apparently sought to generate further libraries. This review will discuss the origins of platensimycin, its mechanism of action, synthetic schemes and where the future may take us following this fascinating discovery.
Asunto(s)
3-Oxoacil-(Proteína Transportadora de Acil) Sintasa/antagonistas & inhibidores , Adamantano/farmacología , Aminobenzoatos/farmacología , Anilidas/farmacología , Antiinfecciosos/farmacología , Adamantano/síntesis química , Adamantano/química , Aminobenzoatos/síntesis química , Aminobenzoatos/química , Aminofenoles/síntesis química , Aminofenoles/química , Aminofenoles/farmacología , Anilidas/síntesis química , Anilidas/química , Animales , Antiinfecciosos/síntesis química , Antiinfecciosos/química , Ácidos Grasos/biosíntesis , Ácidos Grasos/química , Humanos , Estructura Molecular , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/química , Compuestos Policíclicos/farmacología , Relación Estructura-ActividadRESUMEN
Hydrogen bonding interactions play a major role in many chemical and biological processes. This article describes the development of a method for the quantitative estimation of the hydrogen-bonding donor strengths of OH/NH moieties and of the hydrogen bonding acceptor strengths of O/N atoms in different chemical structures. The method is based on the correlation of experimentally observed hydrogen-bonding strengths with quantum-mechanical derived properties, calculated on the acceptor atom (for hydrogen-bond acceptors) and on the heavy atom attached to the donor hydrogen (for hydrogen-bond donors). The properties giving the best correlation with the experimental hydrogen bonding scales were electrophilic superdelocalizability and self-atom polarizability. The best equations found have been implemented in a Web-based tool for hydrogen-bond strength prediction.
Asunto(s)
Diseño de Fármacos , Enlace de Hidrógeno , Programas Informáticos , Gráficos por Computador , Simulación por Computador , Bases de Datos como Asunto , Modelos Químicos , Protones , Teoría CuánticaRESUMEN
A series of novel matrix metalloproteinase inhibitors is described in which selectivity between MMP and 'sheddase' activity has been achieved and which demonstrate potent in vivo activity in models of arthritis and cancer.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Ácidos Hidroxámicos/farmacología , Inhibidores de la Metaloproteinasa de la Matriz , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/uso terapéutico , Melanoma Experimental/tratamiento farmacológico , RatonesRESUMEN
The design and synthesis of a series of analogues of sialyl Lewis(x)(1) which incorporate conformationally rigid tetralin and naphthalene ring systems(2-4) has led to novel compounds which have similar potency to 1 as inhibitors of cell adhesion.
Asunto(s)
Endotelio Vascular/fisiología , Oligosacáridos/química , Oligosacáridos/síntesis química , Conformación de Carbohidratos , Secuencia de Carbohidratos , Adhesión Celular/efectos de los fármacos , Adhesión Celular/fisiología , Células Cultivadas , Gráficos por Computador , Diseño de Fármacos , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Fucosa , Células HL-60 , Humanos , Indicadores y Reactivos , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Molecular , Naftalenos , Oligosacáridos/farmacología , Antígeno Sialil Lewis X , Relación Estructura-Actividad , Tetrahidronaftalenos , Factor de Necrosis Tumoral alfa/farmacología , Venas UmbilicalesRESUMEN
The origins and operation of artificial neural networks are briefly described and their early application to data modelling in drug design is reviewed. Four problems in the use of neural networks in data modelling are discussed, namely overfitting, chance effects, overtraining and interpretation, and examples are given of the means by which the first three of these may be avoided. The use of neural networks as a variable selection tool is shown and the advantage of networks as a nonlinear data modelling device is discussed. The display of multivariate data in two dimensions employing a neural network is illustrated using experimental and theoretical data for a set of charge transfer complexes.
Asunto(s)
Diseño de Fármacos , Modelos Estadísticos , Redes Neurales de la Computación , Interpretación Estadística de Datos , Estructura Molecular , Programas InformáticosRESUMEN
The use of feed forward back propagation neural networks to perform the equivalent of multiple linear regression has been examined using artificial structured data sets and real literature data. Their predictive ability has been assessed using leave-one-out cross-validation and training/test set protocols. While networks have been shown to fit data sets well, they appear to suffer from a number of disadvantages. In particular, they have performed poorly in prediction for the QSAR data examined here, they are susceptible to chance effects, and the relationships developed by the networks are difficult to interpret. This investigation reports results for one particular form of artificial neural network; other architectures and applications, however, may be more suitable.
Asunto(s)
Redes Neurales de la Computación , Relación Estructura-ActividadRESUMEN
The quantitative structure-activity relationships (QSAR's) of 3 series of arylcyclohexylamines have been investigated using computational chemistry and multivariate statistics. Principal component analysis of the aromatic ring data set demonstrated some clustering of activity categories. Biological activity of the cyclohexane ring data set was correlated with molar refractivity. These findings may be useful for predicting the activity of novel neuroprotective agents.
Asunto(s)
Fenciclidina/análogos & derivados , Fenciclidina/farmacología , Ciclohexanos/farmacología , Modelos Moleculares , Análisis Multivariante , Fenciclidina/química , Piperidinas/farmacología , Relación Estructura-ActividadRESUMEN
Various benzimidazole sulphoxides were chirally resolved employing an amylase-based chiral stationary phase. The structure-property relationships of these compounds were investigated using calculated physicochemical properties, molecular modelling and multivariate statistical techniques. A data set of 254 molecular descriptors was used to represent the series of compounds. Analysis of the data set using principal components analysis and non-linear mapping suggested that the separation factor of each enantiomeric pair was associated with nine molecular properties and, in particular, molar refractivity of the Z substituent and the partial charge of atom 6. The separation factor of a sulphoxide not used in the analysis was well predicted thus suggesting that these models may be used to generalize.
Asunto(s)
Bencimidazoles/química , Antiulcerosos/química , Antiulcerosos/aislamiento & purificación , Bencimidazoles/aislamiento & purificación , Cromatografía Líquida de Alta Presión , Electroquímica , Estructura Molecular , Análisis Multivariante , Programas Informáticos , EstereoisomerismoRESUMEN
The techniques of principal components analysis and non-linear mapping are routinely used by computer chemists at SmithKline Beecham Pharmaceuticals in the process of drug development by relating the structure of a compound to its chemical activity. To our knowledge these techniques had not previously been applied to the association between the structure of a compound and its toxicological properties. Using a series of 12 structurally related compounds (11 were active dopamine mimetics and one was inactive), of which five were known to be teratogenic and seven were non-teratogenic, it was possible to demonstrate that molecular modelling techniques could be applied to differentiate toxicological data. The structure/property relationships of these compounds were investigated using calculated physicochemical properties, molecular modelling and multivariate statistical techniques. A data set of 56 molecular descriptors was used to represent this series of compounds. Analysis of the data set using principal components analysis and non-linear mapping suggested that teratogenicity was associated with four molecular properties. Moreover, the electronic nature of the 4-phenyl group appeared to be an important determinant of the teratogenesis.
Asunto(s)
Dopaminérgicos/toxicidad , Modelos Químicos , Anomalías Inducidas por Medicamentos/etiología , Fenómenos Químicos , Química Física , Computadores , Modelos Biológicos , Modelos Moleculares , Análisis Multivariante , Relación Estructura-ActividadRESUMEN
Anatoxin-a (AnTX) is a highly potent agonist acting at the nicotinic acetylcholine receptor (nAChR) and represents a valuable tool in the study of this receptor. Molecular mechanics, semi-empirical and ab initio molecular orbital energy minimization procedures were conducted to investigate the conformation of AnTX. For each minimization procedure, the s-trans enone isomer of protonated AnTX was the energetically favoured conformer due to intramolecular electrostatic interactions. Our studies are discussed in the light of previous experimental observations and conformational studies, in addition to their importance in the development of future pharmacophore models for nAChR agonist binding.
Asunto(s)
Toxinas Bacterianas/química , Toxinas Marinas/química , Toxinas Bacterianas/metabolismo , Toxinas de Cianobacterias , Toxinas Marinas/metabolismo , Microcistinas , Modelos Químicos , Conformación Molecular , Receptores Nicotínicos/metabolismo , Programas Informáticos , Estereoisomerismo , Termodinámica , TropanosRESUMEN
The possible heterogeneity of the agonist and glycine sites of the N-methyl-D-aspartate (NMDA) receptor-complex was examined using receptor binding techniques. Binding of [3H]L-glutamate [( 3H]GLU) and [3H]glycine to synaptic membranes of cerebral and cerebellar cortices, and membranes of a granule cell preparation of rat cerebellum, was characterized. [3H]Glycine always labelled a single population of sites; densities of binding sites (Bmax) in cortical, cerebellar and "granule" membranes were 3.1, 0.87 and 3.6 pmol/mg protein, respectively. Dissociation constants (Kd) in the same three preparations were 0.13, 0.31 and 1.9 microM, respectively. In competition studies, D-cycloserine, but not D-serine and 7-chlorokynurenate, showed varying potency between the membrane preparations, and analysis of variance (ANOVA) revealed a significant interaction between ligands and membrane fractions. Binding of [3H]GLU was saturable and to a single population of sites: Kd 0.5-0.9 microM and Bmax 3.2-3.6 pmol/mg protein. In all three membrane preparations the rank order of potency of NMDA agonists as inhibitors of the binding of [3H]GLU was always L-aspartate greater than L-cysteate greater than L-cysteinesulphinate greater than L-serine-O-sulphate greater than ibotenate greater than L-homocysteate. NMDA, quinolinate and competitive NMDA antagonists were only weak inhibitors of the binding of [3H]GLU and never fully inhibited specific binding. Other subtype-selective excitatory amino acids were very weak or ineffective inhibitors of binding. Binding of NMDA agonists was better described by a two site model whereby the proportion of high affinity sites did not vary significantly across the three membrane preparations.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Glutamatos/metabolismo , Glicina/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Autorradiografía , Unión Competitiva/efectos de los fármacos , Corteza Cerebelosa/anatomía & histología , Corteza Cerebelosa/metabolismo , Corteza Cerebral/anatomía & histología , Corteza Cerebral/metabolismo , Cicloserina/farmacología , Glutamatos/farmacocinética , Ácido Glutámico , Glicina/farmacocinética , Técnicas In Vitro , Ácido Quinurénico/análogos & derivados , Ácido Quinurénico/farmacología , Ligandos , Masculino , Ratas , Ratas Endogámicas , Receptores de Aminoácidos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Serina/metabolismoRESUMEN
The regulation of the central sigma-binding site was investigated using both in vitro and in vivo manipulations in conjunction with radioligand binding. The displacement of the binding of R(+)-[3H]3-[3-hydroxyphenyl]-N-(1-propyl)piperidine [R(+)-[3H]3-PPP] to cortical homogenates by a range of drugs was consistent with the site labelled being a sigma-receptor. (+)-SKF 10,047, (-)-SKF 10,047, (+/-)-cyclazocine, phencyclidine, and dexoxadrol displaced R(+)-[3H]3-PPP with pseudo-Hill coefficients of less than 1. Further analysis employing nonlinear curve fitting techniques demonstrated that displacement data for these compounds were described better by a model whereby R(+)-[3H]3-PPP was displaced from two discrete sites; approximately 65% of the total sites were in the high-affinity state. In the presence of 10 mM Mg2+ and 0.3 mM GTP, displacement curves for (+)-SKF 10,047 and (+/-)-cyclazocine were shifted to the right. These findings were due to the shift of some 15% of the high-affinity binding sites to a low-affinity state. Saturation experiments revealed that 0.3 mM GTP acted competitively to decrease the affinity of R(+)-[3H]3-PPP for the sigma sites. The sigma-binding site was thus likely to be linked to a guanine nucleotide regulatory (G) protein. Thus sigma drugs could be subdivided on the basis of their GTP sensitivity and pseudo-Hill coefficients, and by analogy with other receptors R(+)-3-PPP, (+)-SKF 10,047, and (+/-)-cyclazocine, may be putative sigma-agonists. 1,3-Di(2-tolyl)guanidine (DTG), rimcazole, and haloperidol displaced R(+)-[3H]3-PPP with pseudo-Hill coefficients of approximately unity and thus may be sigma-antagonists. Subchronic treatment with rimcazole was characterized by slight sedation and a concomitant up-regulation, with a decrease in the affinity, of sigma-binding sites. The schedule of rimcazole also increased dopamine turnover in the nucleus accumbens; both the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC) and the DOPAC/dopamine ratio were elevated. DTG produced similar alterations to the binding parameters of the sigma-binding site; however, changes were not observed in general behavior or accumbal dopamine turnover. sigma-Receptors are likely to be linked to a G protein and are functionally involved in the CNS.