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C R Beddell

Publications and source records attributed to C R Beddell.

At least 37 records · Page 2Linked to original sources
PubMed1991

Application of pattern recognition methods to the analysis and classification of toxicological data derived from proton nuclear magnetic resonance spectroscopy of urine.

A computer-based pattern recognition (PR) approach has been applied to the classification and interrogation of 1H NMR-generated urinalysis data, in a variety of experimental toxicity states in the rat. 1H NMR signal intensities for each endogenous urinary metabolite were regarded as coordinates in multidimensional space and analyzed using PR methods, through which the dimensionality was reduced for display and categorization purposes. The changes in the NMR spectral patterns were characterized by 17 metabolic dimensions, which were then analyzed by employing the unsupervised learning methods of hierarchical cluster analysis, two-dimensional nonlinear map (NLM) analysis, and two- or three-dimensional principal components analysis (PCA). Different types of toxin (hepatotoxins and cortical and papillary nephrotoxins) were classified according to NMR-detectable biochemical effects. PCA provided consistently better results than NLMs in terms of discrimination of toxicity type, and maps based on correlation matrices also gave improved discrimination over those based on raw data. Various refinements in the data analysis were investigated, including taking NMR urinalysis data at three time points after exposure of the rats to six different nephrotoxins, as well as employing a dual-scoring system (time and magnitude of change). The maps generated from the time-course information produced the best discrimination between nephrotoxins from different classes. The robustness of the classification methods (in particular NLMs and PCA based on correlation matrices) and the influence of the addition of new scored biochemical data, reflecting dose-response situations, nutritional effects on toxicity, sex differences in biochemical response to toxins, the addition of a new toxin class (cadmium chloride, a testicular toxin and renal carbonic anhydrase inhibitor), and an additional metabolite descriptor (creatine), to the PR analysis were also evaluated. Initial training set maps were fundamentally stable to the addition of new data, and both NLM and PCA methods correctly "predicted" the toxicological effects from NMR data for test compounds, suggesting that the approach using PR and 1H NMR urinalysis for the generation and classification of acute toxicological data has wide applicability.

Animals↗
PubMed1990

Pattern recognition analysis of high resolution 1H NMR spectra of urine. A nonlinear mapping approach to the classification of toxicological data.

A computer-based pattern recognition (PR) approach has been applied to the interpretation of 1H NMR generated urinalysis data in a variety of experimental toxicity states in the rat. 1H NMR signal intensities for each endogenous metabolite in urine were regarded as coordinates in multi-dimensional space and analysed using computer pattern recognition methods through which the dimensionality was reduced for display and categorization purposes. Initially 17 metabolic dimensions were used which were defined by the scored relative concentrations of a variety of urinary metabolites detected in 1H NMR spectra. By employing the unsupervised learning methods of 2- and 3-dimensional nonlinear mapping (NLM) different types of toxin (hepatotoxins, cortical and papillary nephrotoxins) could be classified according to NMR-detectable biochemical effects in the urine. The robustness of the classification methods, and the influence of the addition of new scored biochemical data reflecting dose response situations, nutritional effects on toxicity, sex differences in biochemical response to toxins and addition of a new toxin class (testicular toxin) to the pattern recognition analysis were also evaluated. We find that the initial training set maps are fundamentally stable to the addition of all data types and that the PR methods correctly 'predicted' the toxicological effects of the test compounds. These results confirm the power and wide applicability of linked PR and 1H NMR urinalysis as an approach to the generation and classification of acute toxicological data.

Animals↗
PubMed1990

Neutralizing antibodies to all seven serotypes of foot-and-mouth disease virus elicited by synthetic peptides.

Uncoupled peptides from all seven serotypes of foot-and-mouth disease virus (FMDV) protein VP1 have been used to elicit neutralizing antibody responses in guinea-pigs. The responses were largely serotype specific, although some significant cross-neutralization was observed. Dimeric tandem peptides have also been used to simultaneously elicit neutralizing antibodies to two different FMDV serotypes. The possible existence of structural features common to the B-cell neutralization sites or the guinea-pig helper T-cell sites within all seven peptides are analysed and discussed.

Amino Acid Sequence↗
PubMed1987

The structure of mouse L1210 dihydrofolate reductase-drug complexes and the construction of a model of human enzyme.

The structure of mouse L1210 dihydrofolate reductase (DHFR) complexed with NADPH and trimethoprim has been refined at 2.0 A resolution. The analogous complex with NADPH and methotrexate has been refined at 2.5 A resolution. These structures reveal for the first time details of drug interactions with a mammalian DHFR, which are compared with those observed from previous X-ray investigations of DHFR/inhibitor complexes. The refined L1210 structure has been used as the basis for the construction of a model of the human enzyme. There are only twenty-one sequence differences between mouse L1210 and human DHFRs, and all but two of these are located close to the molecular surface: a strong indication that the active sites are essentially identical in these two mammalian enzymes.

Animals↗
PubMed1986

Crystallographic investigation of the cooperative interaction between trimethoprim, reduced cofactor and dihydrofolate reductase.

The structure of the complex between E. coli (RT500) form I dihydrofolate reductase, the antibacterial trimethoprim and NADPH has been determined by X-ray crystallography. The inhibitor and cofactor are in mutual contact. A flexible chain segment which includes Met 20 is in contact with the inhibitor in the presence of NADPH, but more distant in its absence. By contrast, the inhibitor conformation is little changed with NADPH present. We discuss these observations with regard to the mutually cooperative binding of these ligands to the protein, and to the associated enhancement of inhibitory selectivity shown by trimethoprim for bacterial as opposed to vertebrate enzyme.

Binding Sites↗
PubMed1985

Refined crystal structures of Escherichia coli and chicken liver dihydrofolate reductase containing bound trimethoprim.

Refined crystal structures are reported for complexes of Escherichia coli and chicken dihydrofolate reductase containing the antibiotic trimethoprim (TMP). Structural comparison of these two complexes reveals major geometrical differences in TMP binding that may be important in understanding the stereo-chemical basis of this inhibitor's selectivity for bacterial dihydrofolate reductases. For TMP bound to chicken dihydrofolate reductase we observe an altered binding geometry in which the 2,4-diaminopyrimidine occupies a position in closer proximity (by approximately 1 A) to helix alpha B compared to the pyrimidine position for TMP or methotrexate bound to E. coli dihydrofolate reductase. One important consequence of this deeper insertion of the pyrimidine into the active site of chicken dihydrofolate reductase is the loss of a potential hydrogen bond that would otherwise form between the carbonyl oxygen of Val-115 and the inhibitor's 4-amino group. In addition, for TMP bound to E. coli dihydrofolate reductase, the inhibitor's benzyl side chain is positioned low in the active-site pocket pointing down toward the nicotinamide-binding site, whereas, in chicken dihydrofolate reductase, the benzyl group is accommodated in a side channel running upward and away from the cofactor. As a result, the torsion angles about the C5-C7 and C7-C1' bonds for TMP bound to the bacterial reductase (177 degrees, 76 degrees) differ significantly from the corresponding angles for TMP bound to chicken dihydrofolate reductase (-85 degrees, 102 degrees). Finally, when TMP binds to the chicken holoenzyme, the Tyr-31 side chain undergoes a large conformational change (average movement is 5.4 A for all atoms beyond C beta), rotating down into a new position where it hydrogen bonds via an intervening water molecule to the backbone carbonyl oxygen of Trp-24.

Animals↗
PubMed1985

Receptor-based design of dihydrofolate reductase inhibitors: comparison of crystallographically determined enzyme binding with enzyme affinity in a series of carboxy-substituted trimethoprim analogues.

By the use of molecular models of Escherichia coli dihydrofolate reductase (DHFR), analogues of trimethoprim (TMP) were designed which incorporated various 3'-carboxyalkoxy moieties in order to acquire ionic interactions with positively charged active-site residues. Certain of these compounds have shown exceptionally high affinity for this enzyme. For example, the 3'-(carboxypentyl)oxy analogue was found to be 55-fold more inhibitory than TMP toward E. coli DHFR (Ki = 0.024 nM vs. 1.32 nM for TMP). X-ray crystallographic studies of E. coli DHFR in binary complexes with TMP and two members of this acid-containing series of compounds defined the binding of these inhibitors and showed the carboxyl group of the latter two inhibitors to be ionically bound to Arg-57. These observations were in agreement with postulated binding modes that were based on receptor modeling.

Binding Sites↗
PubMed1984

Substituted benzaldehydes designed to increase the oxygen affinity of human haemoglobin and inhibit the sickling of sickle erythrocytes.

Substituted benzaldehydes have been designed to bind preferentially to the oxy conformation of human haemoglobin at a site between the amino terminal residues of the alpha-subunits. Such compounds should stabilize the oxygenated form of haemoglobin and thereby increase its oxygen affinity. The compounds produce the expected effect, left-shifting the oxygen saturation curve of dilute haemoglobin solutions and of whole blood, although the binding pattern to haemoglobin is more complex than envisaged by the design hypothesis. The predicted best compound is also a potent inhibitor, at low oxygen pressure, of the sickling of erythrocytes from patients homozygous for sickle cell disease, and may prove to be a clinically useful anti-sickling agent.

2,3-Diphosphoglycerate↗
PubMed1979

Base pairing in messenger RNA's for small peptides.

Longest runs of Watson-Crick pairing in hypothetical m-RNA's for a number of natural peptides were no greater than those in the hypothetical m-RNA's for a large number of randomized amino acid sequences from these peptides. This shown that even if base-pairing in m-RNA were a biological requirement, it would little constrain the amino acid sequence.

Amino Acid Sequence↗
PubMed1979

Species differences in the binding of compounds designed to fit a site of known structure in adult human haemoglobin.

1. Oxygen dissociation curves are reported for human haemoglobins A1, FII, FI, A1c and Raleigh (beta1 valine leads to acetylalanine) and for horse haemoglobin in the absence and presence of 2,3-diphosphoglycerate (DPG), or 4,4'-diformyl-2-bibenzyl oxyacetic acid, or the bisulphite addition compound of the latter. 2. These haemoglobins were selected because their amino acid sequences are different at the DPG receptor site of human adult deoxyhaemoglobin. 3. The size of the shifts of the dissociation curves are in the sequence expected from the postulated numbers of interactions made by each compound with each haemoglobin type, based on the assumption of a common receptor site for the three compounds. 4. Multiple linear regression analysis shows that the free energies of interaction of the compounds with the haemoglobins may be predicted, to a first approximation, by summing the number of ionic and covalent bonds predicted for each effector-receptor combination, a reversible covalent bond contributing about twice as much energy (-6.78 kJmol-1) as an ionic interaction (-3.14 kJmol-1).

Adult↗
PubMed1977

Symmetry in prostaglandins.

Observations of the agonist activity of prostaglandins on the guinea-pig ileum are analysed. The structure-activity relationships are interpreted in relation to the approximate diad axis of symmetry in the molecules. It is suggested that some receptors for prostaglandins may have a perfect diad axis of symmetry between identical protein subunits.

Allosteric Site↗