Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Analysis of the interactions between an enzyme and multiple inhibitors using combination plots.

ABSTRACT: The concurrent effects of two enzyme inhibitors have been analysed previously with the Yonetani-Theorell plot to obtain insight into the interactions between bound inhibitors. This procedure, like many other traditional graphical methods in enzymology, is based on the estimation of intersecting tendencies in a family of lines. In a recent paper from this laboratory [Chan (1995) Biochem. J. 311, 981-985] it was shown that a plot of this nature may sometimes be replaced, with advantage, by a 'combination plot' in which all data points are accommodated in a single line. We have now extended this approach to analyse the effects of multiple inhibitors and have developed combination plots which illustrate the interaction behaviour in an optimal manner. Thus, in these plots, the synergistic or antagonistic nature of the interactions is clearly evident from the slope, which also provides a direct estimate of the interaction coefficient. The analysis is more efficient and consequently requires fewer enzyme assays. This approach is applicable to various special cases, including that in which three inhibitors bind simultaneously to the enzyme.

SUBMITTER: Asante-Appiah E

PROVIDER: S-EPMC1217892 | biostudies-other | 1996 Nov

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

Combination plots as graphical tools in the study of enzyme inhibition.

Project description:Although statistical regression has become the method of choice in the analysis of enzyme kinetics, graphical methods continue to be useful on account of their illustrative capabilities. It is pointed out in this paper that enzyme inhibition data may be presented more efficiently as a single linear plot than the traditional way as a family of lines. This approach has been taken previously by Hunter and Downs [Hunter and Downs (1945) J. Biol. Chem. 157, 427-446] but has remained neglected. A new version of this type of plot (combination plot) has been devised which is linear for competitive, non-competitive, uncompetitive and linear mixed inhibition and has a characteristic appearance for each type of inhibition behaviour. The slopes and intercepts not only indicate directly the dissociation constant but also provide quantitative criteria for the nature of inhibition. This plot should serve as a useful graphical tool in enzyme research as well as in biochemical education.

| S-EPMC1136098 | biostudies-other

Visualizing Multiple Quantile Plots.

Project description:Multiple-quantile plots provide a powerful graphical method for comparing the distributions of two or more populations. This article develops a method of visualizing triple-quantile plots and their associated confidence tubes, thus extending the notion of a quantile-quantile (QQ) plot to three dimensions. More specifically, we consider three independent one-dimensional random samples with corresponding quantile functions Q1, Q2, and Q3. The triple-quantile (QQQ) plot is then defined as the three-dimensional curve Q(p) = (Q1(p), Q2(p), Q3(p)), where 0 < p < 1. The empirical likelihood method is used to derive simultaneous distribution-free confidence tubes for Q. We apply our method to an economic case study of strike durations and to an epidemiological study involving the comparison of cholesterol levels among three populations. These data as well as the Mathematica code for computation of the tubes are available in the online supplementary materials.

| S-EPMC3899392 | biostudies-literature

Visualising disease progression on multiple variables with vector plots and path plots.

Project description:BackgroundIt is often desirable to observe how a disease progresses over time in individual patients, rather than graphing group averages; and since multiple outcomes are typically recorded on each patient, it would be advantageous to visualise disease progression on multiple variables simultaneously.MethodsA variety of vector plots and a path plot have been developed for this purpose, and data from a longitudinal Huntington's disease study are used to illustrate the utility of these graphical methods for exploratory data analysis.ResultsInitial and final values for three outcome variables can be easily visualised per patient, along with the change in these variables over time. In addition to the disease trajectory, the path individual patients take from initial to final observation can be traced. Categorical variables can be coded with different types of vectors or paths (e.g. different colours, line types, line thickness) and separate panels can be used to include further categorical or continuous variables, allowing clear visualisation of further information for each individual. In addition, summary statistics such as mean vectors, bivariate interquartile ranges and convex polygons can be included to assist in interpreting trajectories, comparing groups, and detecting multivariate outliers.ConclusionVector and path plots are useful graphical methods for exploratory data analysis when individual-level information on multiple variables over time is desired, and they have several advantages over plotting each variable separately.

| S-EPMC2693505 | biostudies-literature

Comprehensive analysis of LC/MS data using pseudocolor plots.

Project description:We have developed new applications of the pseudocolor plot for the analysis of LC/MS data. These applications include spectral averaging, analysis of variance, differential comparison of spectra, and qualitative filtering by compound class. These applications have been motivated by the need to better understand LC/MS data generated from analysis of human biofluids. The examples presented use data generated to profile steroid hormones in urine extracts from a Cushing's disease patient relative to a healthy control, but are general to any discovery-based scanning mass spectrometry technique. In addition to new visualization techniques, we introduce a new metric of variance: the relative maximum difference from the mean. We also introduce the concept of substructure-dependent analysis of steroid hormones using precursor ion scans. These new analytical techniques provide an alternative approach to traditional untargeted metabolomics workflow. We present an approach to discovery using MS that essentially eliminates alignment or preprocessing of spectra. Moreover, we demonstrate the concept that untargeted metabolomics can be achieved using low mass resolution instrumentation.

| S-EPMC4141469 | biostudies-other

Interactions between inhibitors of dihydrofolate reductase.

Project description:The binding of substrates and inhibitors to dihydrofolate reductase was studied by steady-state kinetics and high-field 1H-n.m.r. spectroscopy. A series of 5-substituted 2,4-diaminopyrimidines were examined and were found to be 'tightly binding' inhibitors of the enzyme (Ki less than 10(-9) M). Studies on the binding of 4-substituted benzenesulphonamides and benzenesulphonic acids also established the existence of a 'sulphonamide-binding site' on the enzyme. Subsequent n.m.r. experiments showed that there are two binding sites for the sulphonamides on the enzyme, one of which overlaps the coenzyme (NADPH) adenine-ring-binding site. An examination of the pH-dependence of the binding of sulphonamides to the enzyme indicated the influence of an ionizable group on the enzyme that was not directly involved in the sulphonamide binding. The change in pKa value from 6.7 to 7.2 observed on sulphonamide binding suggests the involvement of a histidine residue, which could be histidine-28.

| S-EPMC1138366 | biostudies-other

Three-Dimensional Analysis of the Interactions between hLDH5 and Its Inhibitors.

Project description:Inhibitors of human lactate dehydrogenase (hLDH5)-the enzyme responsible for the conversion of pyruvate to lactate coupled with oxidation of NADH to NAD?-are promising therapeutic agents against cancer because this enzyme is generally found to be overexpressed in most invasive cancer cells and is linked to their vitality especially under hypoxic conditions. Consequently, significant efforts have been made for the identification of small-molecule hLDH5 inhibitors displaying high inhibitory potencies. X-ray structure of hLDH5 complexes as well as molecular modeling studies contribute to identify and explain the main binding modes of hLDH5 inhibitors reported in literature. The purpose of this review is to analyze the main three-dimensional interactions between some of the most potent inhibitors and hLDH5, in order to provide useful suggestions for the design of new derivatives.

| S-EPMC6149858 | biostudies-literature

Combination of epigenetic enzyme inhibitors, GSKJ4 and Belinostat, reveals efficacy in IDH1 mutant gliomas

Project description:Mutations in IDH1 and IDH2 genes are very common in low grade gliomas and secondary GBM. They induce hypermethylation of DNA and histones in tumor cells, and generate a specific epigenetic phenotype. Therefore, we decided to perform a chemical screen consisting of inhibitors of epigenetic regulators on patient-derived IDH mutant cell lines. Dual combinations of hit inhibitors in low doses were also analyzed to increase treatment efficiency. Individual and combinatorial effects of these inhibitors were also analyzed in wild type and IDH mutant pair of A172 GBM cell line that was derived by ectopic overexpression of mutant IDH1. GSK-J4 and Belinostat combination was highly effective on both patient-derived and engineered IDH mutant cells compared to wild type cells. Interestingly, sensitized IDH mutant cells were recovered via mutant IDH inhibitor, GSK864, which is thought as a candidate drug for IDH mutant glioma. On the other hand, viability of non-malignant fibroblasts were not affected from these drugs in these doses. GSK-J4 and Belinostat combination induce apoptosis which was shown by increased Caspase 3/7 activity, PARP cleavage and recovery with general caspase inhibitor (Z-VAD-FMK). Change in histone modifications such as H3K4me3, H3K9me3, H3K27me3 and H3K27ac were observed after mutant IDH overexpression and also drug treatments. RNA-seq and GSEA analysis revealed activation of unfolded protein and viral response pathways in IDH mutant cells which indicate increased cell stress. GSKJ4 and Belinostat induces cell cycle arrest and apoptosis by further increasing cell stress probably because of dramatic changes in chromatin structure.

2024-07-14 | GSE134120 | GEO

Using siRNA to define functional interactions between melanopsin and multiple G Protein partners.

Project description:Melanopsin expressing photosensitive retinal ganglion cells (pRGCs) represent a third class of ocular photoreceptors and mediate a range of non-image forming responses to light. Melanopsin is a G protein coupled receptor (GPCR) and existing data suggest that it employs a membrane bound signalling cascade involving Gnaq/11 type G proteins. However, to date the precise identity of the Gα subunits involved in melanopsin phototransduction remains poorly defined. Here we show that Gnaq, Gna11 and Gna14 are highly co-expressed in pRGCs of the mouse retina. Furthermore, using RNAi based gene silencing we show that melanopsin can signal via Gnaq, Gna11 or Gna14 in vitro, and demonstrate that multiple members of the Gnaq/11 subfamily, including Gna14 and at least Gnaq or Gna11, can participate in melanopsin phototransduction in vivo and contribute to the pupillary light responses of mice lacking rod and cone photoreceptors. This diversity of G protein interactions suggests additional complexity in the melanopsin phototransduction cascade and may provide a basis for generating the diversity of light responses observed from pRGC subtypes.

| S-EPMC4282707 | biostudies-literature

Clinical implications of trials investigating drug-drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs.

Project description:Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut syndrome or Dravet syndrome in randomized, double-blind, add-on, controlled phase 3 trials. It is important to consider the possibility of drug-drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved in drug metabolism of common antiseizure drugs (ASDs). CBD did not affect CYP3A4 activity. Induction of CYP3A4 and CYP2C19 led to small reductions in exposure to CBD and its major metabolites. Inhibition of CYP3A4 activity did not affect CBD exposure and caused small increases in exposure to CBD metabolites. Inhibition of CYP2C19 activity led to a small increase in exposure to CBD and small decreases in exposure to CBD metabolites. One potentially clinically important DDI was identified: combination of CBD and clobazam (CLB) did not affect CBD or CLB exposure, but increased exposure to major metabolites of both compounds. Reduction of CLB dose may be considered if adverse reactions known to occur with CLB are experienced when it is coadministered with CBD. There was a small increase of exposure to stiripentol (STP) when coadministered with CBD. STP had no effect on CBD exposure but led to minor decreases in exposure to CBD metabolites. Combination of CBD and valproate (VPA) did not cause clinically important changes in the pharmacokinetics of either drug, or 2-propyl-4-pentenoic acid. Concomitant VPA caused small increases in exposure to CBD metabolites. Dose adjustments are not likely to be necessary when CBD is combined with STP or VPA. The safety results from these trials were consistent with the known safety profile of CBD. These trials indicate an overall low potential for DDIs between CBD and other ASDs, except for CLB.

| S-EPMC7693203 | biostudies-literature

Using combination therapy to override stromal-mediated chemoresistance in mutant FLT3-positive AML: synergism between FLT3 inhibitors, dasatinib/multi-targeted inhibitors and JAK inhibitors.

Project description:Acute myeloid leukemia (AML) progenitors are frequently characterized by activating mutations in the receptor tyrosine kinase Fms-like tyrosine kinase-3 (FLT3). Protein tyrosine kinases are integral components of signaling cascades that have a role in both FLT3-mediated transformation as well as viability pathways that are advantageous to leukemic cell survival. The bone marrow microenvironment can diminish AML sensitivity to tyrosine kinase inhibitors. We hypothesized that inhibition of protein kinases in addition to FLT3 may be effective in overriding drug resistance in AML. We used a cell-based model mimicking stromal protection as part of an unbiased high-throughput chemical screen to identify kinase inhibitors with the potential to override microenvironment-mediated drug resistance in mutant FLT3-positive AML. Several related multi-targeted kinase inhibitors, including dasatinib, with the capability of reversing microenvironment-induced resistance to FLT3 inhibition were identified and validated. We validated synergy in vitro and demonstrated effective combination potential in vivo. In particular Janus kinase inhibitors were effective in overriding stromal protection and potentiating FLT3 inhibition in primary AML and cell lines. These results hint at a novel concept of using combination therapy to override drug resistance in mutant FLT3-positive AML in the bone marrow niche and suppress or eradicate residual disease.

| S-EPMC4054699 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data