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Biomedical subjects

S L Price

Publications and source records attributed to S L Price.

At least 19 recordsLinked to original sources
PubMed2001

The prediction, morphology, and mechanical properties of the polymorphs of paracetamol.

The analgesic drug paracetamol (acetaminophen) has two reported metastable polymorphs, one with better tableting properties than the stable form, and another which remains uncharacterized. We have therefore performed a systematic crystal structure prediction search for minima in the lattice energy of crystalline paracetamol. The stable monoclinic form is found as the global lattice-energy minimum, but there are at least a dozen energetically feasible structures found, including the well-characterized metastable orthorhombic phase. Hence, we require additional criteria to reduce the number of hypothetical crystal structures that can be considered as potential polymorphs. For this purpose the elastic properties and vapor growth morphology of the known and predicted structures have been estimated using second-derivative analysis and the attachment-energy model. These inexpensive calculations give reasonable agreement with the available experimental data for the known polymorphs. Some of the hypothetical structures are predicted to have a low growth rate and plate-like morphology, and so are unlikely to be observed. Another is only marginally mechanically stable. Thus, this first consideration of such properties in a crystal-structure prediction study appears to reduce the number of predicted polymorphs while leaving a few candidates for the uncharacterized form.

Acetaminophen↗
PubMed2001

Knowledge integration: insight through the E-portal.

Data become information when they can be summarized and organized into logical patterns; information becomes knowledge when it can be manipulated for actionable decision making; knowledge becomes insight when contextually relevant and temporarily appropriate. This article describes how information technology can now be used to provide clinicians with access to both insight and information that is context- and event-sensitive. Collaboration between the American College of Physicians, medical knowledge experts, Oregon Health Sciences University (OHSU), and shared medical systems for framework and infrastructure combine to create the ideal environment of complementary and synergistic competencies. This article describes the research that is under way at OHSU to determine how to deploy medical knowledge derived from these sources and integrate it into the clinical workflow; it also examines a vision of how medical knowledge can be integrated in the future.

Education, Medical, Continuing↗
PubMed2001

Diffusion Monte Carlo simulations on uracil-water using an anisotropic atom-atom potential model.

We have developed an anisotropic atom-atom intermolecular potential model for the interaction of uracil with water. The potential consists of a distributed multipole analysis (DMA) model for the electrostatic energy, and a 6-exp potential to represent the repulsion-dispersion term. The repulsion-dispersion potential parameters are adjusted to yield good agreement with accurate ab initio data on the minima and transition states of the uracil-water complex. We have used this potential in diffusion Monte Carlo simulations of uracil-water, uracil-(water)2 and uracil-(water)3. The uracil-water simulations show that the theoretically based potential gives a qualitatively different picture of uracil hydration than that provided by a standard isotropic atom-atom point charge model, which is shown to underestimate the delocalized motion of the water hydrogen atoms. Plots of the vibrational probability density of the hydrogen atoms show the delocalized motion of the water hydrogen atoms that are not involved in hydrogen bonding.

Journal Article↗
PubMed2000

A test of crystal structure prediction of small organic molecules.

A collaborative workshop was held in May 1999 at the Cambridge Crystallographic Data Centre to test how well currently available methods of crystal structure prediction perform when given only the atomic connectivity for an organic compound. A blind test was conducted on a selection of four compounds and a wide range of methodologies representing, the principal computer programs currently available were used. There were 11 participants who were allowed to propose at most three structures for each compound. No program gave consistently reliable results. However, seven proposed structures were close to an experimental one and were classified as "correct". One compound occurred in two polymorphs, but only one form was predicted correctly among the calculated structures. The basic problem with lattice energy based methods of crystal structure prediction is that many structures are found within a few kJ mol(-1) of the global minimum. The fine detail of the force-field methodology and parametrization influences the energy ranking within each method. Nevertheless, present methods may be useful in providing a set of structures as possible polymorphs for a given molecular structure.

Journal Article↗
PubMed1999

Electrostatic factors in DNA intercalation.

The factors that determine the binding of a chromophore between the base pairs in DNA intercalation complexes are dissected. The electrostatic potential in the intercalation plane is calculated using an accurate ab initio based distributed multipole electrostatic model for a range of intercalation sites, involving different sequences of base pairs and relative twist angles. There will be a significant electrostatic contribution to the binding energy for chromophores with a predominantly positive electrostatic potential, but this varies significantly with sequence, and somewhat with twist angle. The usefulness of these potential maps for understanding the binding of intercalators is explored by calculating the electrostatic binding energy for 9-aminoacridine, ethidium, and daunomycin in a variety of model binding sites. The electrostatic forces play a major role in the positioning of an intercalating 9-aminoacridine and a significant stabilizing role in the binding of ethidium in its sterically constrained position, but the intercalation of daunomycin is determined by the side-chain binding. Sequence preferences are likely to be determined by a complex and subtle mixture of effects, with electrostatics being just one component. The electrostatic binding energy is also unlikely to be a major determinant of the twist angle, as its variation with angle is modest for most intercalation sites. Overall, the electrostatic potential maps give guidance on how positively charged chromophores can be chemically adapted by heteroatomic substitution to optimise their binding.

Aminacrine↗
PubMed1999

Filtering Web pages for quality indicators: an empirical approach to finding high quality consumer health information on the World Wide Web.

The World Wide Web is an increasingly popular source for consumer health information, but many authors have expressed concerns about the quality of health information present on the Internet. We have developed a prototype system that responds to a consumer health query by returning a list of Web pages that are ranked according to the likely quality of the page contents. A computer program identifies some of the criteria that have been suggested for assessing the quality of health information on the Internet. It also identifies characteristics that may serve as proxies for desirable (or undesirable) qualities that are difficult to assess directly using an algorithm. Intervening in the search process and automatically analyzing the contents of each page returned by a general search engine may facilitate the search for high quality consumer health information on the Web.

Health Education↗
PubMed1997

The orientation of N-H...O=C and N-H...N hydrogen bonds in biological systems: how good is a point charge as a model for a hydrogen bonding atom?

In order to design new ligands for protein-binding sites of unknown structure, it would be useful to predict the likely sites of hydrogen bonding of an unknown protein fragment to a known molecule. The positions of maxima and minima in the electrostatic potential at appropriate distances from the van der Waals surface were calculated for various small molecules, nucleic acid bases, peptide units and amino acid side chains containing groups which can form the biologically important N-H...O=C and N-H...N hydrogen bonds. Their ability to predict the positions of H and O/N in hydrogen bonded complexes, as predicted by optimising the electrostatic interactions of pairs of such molecules constrained by the molecular shapes, was assessed. It is shown that extrema in the electrostatic potential around the isolated molecules give worthwhile predictions for the locations of hydrogen binding partners. For molecules bound by a single N-H...O=C hydrogen bond, the electrostatic maximum associated with the H is usually less than 1 A from an acceptor atom, while a C=O electrostatic minimum is generally less than 1.5 A from the hydrogen bond proton. However, a significant number of hydrogen bonds form to the opposite lone pair from the electrostatic minimum, in which case the separation is up to 3.3 A. This reflects the broad electrostatic potential well around a carbonyl oxygen between the lone pair directions. The model predicts when neighbouring atoms drastically change the hydrogen bonding characteristics of an N-H or C=O group. Although the geometries of hydrogen bonded complexes are influenced by the other van der Waals contacts between the molecules, particularly multiple hydrogen bonds, these influences are constant when considering hydrogen bonding to a specific uncharacterised binding site. Hence, the consideration of sterically accessible electrostatic extrema will be useful in the design of new ligands.

Amides↗
PubMed1996

On the electrostatic and steric similarity of lactam compounds and the natural substrate for bacterial cell-wall biosynthesis.

Electrostatic and structural properties of a set of beta-lactam, gamma-lactam and nonlactam compounds have been analyzed and compared with those of a model of the natural substrate D-alanyl-D-alanine for the carboxy- and transpeptidase enzymes. This first comparison of the electrostatic properties has been based on a distributed multipole analysis of high-quality ab initio wave functions of the substrate and potential antibiotics. The electrostatic similarity of the substrate and active compounds is apparent, and contrasts with the electrostatic properties of the noninhibitors. This has been quantified to give a reasonable correlation with the MIC (Minimum Concentration for Inhibition) and with kinetic data (k2/K) in accordance with the model for interaction of the lactam compounds with DD-peptidase. These correlations provide a better prediction of antibacterial activity than purely structural criteria.

Amino Acid Sequence↗
PubMed1995

Immunohistochemical detection of A1 adenosine receptors in rat brain with emphasis on localization in the hippocampal formation, cerebral cortex, cerebellum, and basal ganglia.

Polyclonal antisera were generated against two identical regions of rat and human A1 adenosine receptors using synthetic multiple-antigenic-peptides as immunogens. Western blotting showed that the antisera recognized a single protein in brain of the expected size for A1 receptors. Immunohistochemistry of CHO cells transfected with the rat or human A1 adenosine receptor cDNAs showed robust labeling of the cell surface. In contrast, labeling was not apparent over non-transfected CHO cells, nor over CHO cells expressing A2a receptors. The pattern of immunoreactivity in rat brain was similar to that expected for A1 adenosine receptors. In contrast to receptor autoradiography or in situ hybridization methods, immunohistochemistry allowed identification of individually labeled cells and processes. Heavy labeling was apparent in many brain regions. In the hippocampal formation, strong labeling was present on granule cell bodies and dendrites, mossy fibers, and pyramidal neurons. In cerebellum, basket cells were the most heavily labeled cell type. Less intense staining was present over granule cells. In cerebral cortex, pyramidal cells were the most heavily labeled cell type, and some interneurons were also labeled. In the basal ganglia, 43% of neurons in the globus pallidus were labeled. In the caudate-putamen region, 38% of neurons were labeled. Heavy labeling was present in most thalamic nuclei, and moderate to heavy labeling was seen in many brainstem nuclei. These data identify specific cellular sites of A1 receptor expression and support the concept of cellular specificity of A1 adenosine receptor action.

Animals↗
PubMed1995

The matching of electrostatic extrema: a useful method in drug design? A study of phosphodiesterase III inhibitors.

Ligands which bind to a specific protein binding site are often expected to have a similar electrostatic environment which complements that of the binding site. One method of assessing molecular electrostatic similarity is to examine the possible overlay of the maxima and minima in the electrostatic potential outside the molecules and thereby match the regions where strong electrostatic interactions, including hydrogen bonds, with the residues of the binding site may be possible. This approach is validated with accurate calculations of the electrostatic potential, derived from a distributed multiple analysis of an ab initio charge density of the molecule, so that the effects of lone pair and pi-electron density are correctly included. We have applied this method to the phosphodiesterase (PDE) III substrate adenosine-3',5'-cyclic monophosphate (cAMP) and a range of nonspecific and specific PDE III inhibitors. Despite the structural variation between cAMP and the inhibitors, it is possible to match three or four extrema to produce relative orientations in which the inhibitors are sufficiently sterically and electrostatically similar to the natural substrate to account for their affinity for PDE III. This matching of extrema is more apparent using the accurate electrostatic models than it was when this approach was first applied, using semiempirical point charge models. These results reinforce the hypothesis of electrostatic similarity and give weight to the technique of extrema matching as a useful tool in drug design.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Relative binding orientations of adenosine A1 receptor ligands--a test case for Distributed Multipole Analysis in medicinal chemistry.

The electrostatic properties of adenosine-based agonists and xanthine-based antagonists for the adenosine A1 receptor were used to assess various proposals for their relative orientation in the unknown binding site. The electrostatic properties were calculated from distributed multipole representations of SCF wavefunctions. A range of methods of assessing the electrostatic similarity of the ligands were used in the comparison. One of the methods, comparing the sign of the potential around the two molecules, gave inconclusive results. The other approaches, however, provided a mutually complementary and consistent picture of the electrostatic similarity and dissimilarity of the molecules in the three proposed relative orientations. This was significantly different from the results obtained previously with MOPAC AM1 point charges. In the standard model overlay, where the aromatic nitrogen atoms of both agonists and antagonists are in the same position relative to the binding site, the electrostatic potentials are so dissimilar that binding to the same receptor site is highly unlikely. Overlaying the N6-region of adenosine with that near C8 of theophylline (the N6-C8 model) produces the greatest similarity in electrostatic properties for these ligands. However, N6-cyclopentyladenosine (CPA) and 1,3-dipropyl-8-cyclopentyl-xanthine (DPCPX) show greater electrostatic similarity when the aromatic rings are superimposed according to the flipped model, in which the xanthine ring is rotated around its horizontal axis. This difference is mainly attributed to the change in conformation of N6-substituted adenosines and could result in a different orientation for theophylline and DPCPX within the receptor binding site. However, it is more likely that DPCPX also binds according to the N6-C8 model, as this model gives the best steric overlay and would be favoured by the lipophilic forces, provided that the binding site residues could accommodate the different electrostatic properties in the N6/N7-region. Finally, we have shown that Distributed Multipole Analysis (DMA) offers a new, feasible tool for the medicinal chemist, because it provides the use of reliable electrostatic models to determine plausible relative binding orientations.

Adenosine↗
PubMed1995

Solvent interactions with pi ring systems in proteins.

The interaction of water molecules with apolar amino acids is an important aspect of the hydrophobic effect and hence of protein folding. Our distributed multiple electrostatic model for water interacting with phenylalanine dipeptides shows that minimum energy sites exist above the aromatic ring such that a solvent molecule can interact with the pi electrons, but only when this site is not blocked by main-chain atoms or disturbed by main-chain polar atoms. This is consistent with the experimental evidence of others that water can hydrogen bond to aromatic pi electrons. In contrast, our analysis of solvent interactions with phenylalanine residues based on 48 high-resolution, well-refined protein structures shows that the dominant interaction of solvent molecules is with the edge of the ring and not with the pi elections. As the faces of phenylalanine rings tend to be buried, and solvent interactions with neighbouring polar atoms are more favourable, the interaction of water molecules with the faces of aromatic pi rings appears not to occur frequently in proteins.

Crystallography↗
PubMed1994

Amino/aromatic interactions in proteins: is the evidence stacked against hydrogen bonding?

We investigate the suggestion that aromatic rings can act as hydrogen-bond acceptors in proteins, by an analysis of 55 non-homologous high-resolution protein chain structures. Approximately 10% of interactions between sp2 hybridized nitrogen atoms, from either side-chains or main-chains, and phenylalanine or tyrosine rings have the nitrogen atom positioned above the ring. In these instances, however, the sp2 nitrogen atoms tend to form stacked interactions with the aromatic rings, these geometries outnumbering amino/aromatic hydrogen bonds by around 2.5:1. The statistically expected distribution, in contrast, would have only a few stacked structures and many more with larger interplanar angles, corresponding to amino/aromatic hydrogen bonds. Thus, although we do find some of these unconventional hydrogen bonds, they are clearly disfavoured relative to stacked geometries. In stacked geometries, the nitrogen-bearing groups are observed to fulfil their hydrogen-bonding potential by forming conventional, energetically stronger, hydrogen bonds with other groups in protein or solvent. This may explain the favourability of stacking. Thus, although ab initio calculations of the gas phase interaction energies for three model systems generally favour the amino/aromatic hydrogen-bonded over the stacked geometries, the differences are small enough to be outweighed easily by the additional conventional hydrogen bonding in stacked structures.

Amino Acid Sequence↗
PubMed1992

Towards an understanding of the arginine-aspartate interaction.

We have made a comparison of the geometries of intra- and intermolecular arginine-aspartate interactions by extracting orientation information from protein co-ordinate data. The results show a pronounced difference, with both types of interaction preferring to form twin N-H . . . O = C hydrogen bonds, but involving different nitrogen atoms. In intramolecular interactions, the aspartate favours a "side on" geometry, forming hydrogen bonds with N epsilon and N eta 2; in the intermolecular case, however, "end on" contacts involving N eta 1 and N eta 2 of the arginine are preferred. We have used Distributed Multipole Analysis of the methylguanidinium-acetate system to model the electrostatic component of the arginine-aspartate ion pair interaction in vacuo. We find, in agreement with the experimental arginine-aspartate distribution, that side on and end on doubly N-H . . . O = C hydrogen-bonded configurations are clearly the most favourable, with the side on being marginally lower in energy. Thus, despite the many competing side-chain interactions in proteins, many arginine-aspartate pairs adopt one of the minimum electrostatic energy conformations, or one close to a minimum. Within each of the two regions (side on and end on) we find only a small energy gap between the "symmetric" doubly hydrogen-bonded and slightly displaced "staggered" structures, again in agreement with the crystal structure data. Further calculations of the total ab initio interaction energy show that this follows the electrostatic term in its orientational variation, this phenomenon of "electrostatic domination" being well known in hydrogen-bonded systems. The end on arginine nitrogen atoms are observed to be more surface-exposed than N epsilon, as demonstrated by their greater accessibilities over a large sample of proteins. This helps explain the side on and end on preferences of intra- and intermolecular interactions, respectively. We also note the effect of short sequence intervals, particularly i in equilibrium with i + 2 relationships, in forcing many intramolecular contacts to be side on.

Arginine↗
PubMed1991

On the representation of electrostatic fields around ab initio charge distributions.

We compare two methods (Mulliken charges and a distributed multipole analysis, DMA) of representing an ab initio charge distribution for calculating the electrostatic field and potential outside the molecule, using pyrimidine and the RNA base uracil as examples. This is done using a 3-D graphical display of the electrostatic fields, which, when used with real-time rotation, zooming and clipping, has many advantages for qualitatively assessing the electrostatic interactions of a molecule. The errors involved in using Mulliken point charges may be of similar magnitude to the total electrostatic field in regions which are important in recognition processes. The DMA representation automatically includes the anisotropic electrostatic effects of non-spherical features in the charge distribution of each atom, and yet the displayed electrostatic fields around the atoms which have lone-pair density do not show marked anisotropy.

Chemical Phenomena↗
PubMed1988

Isoflurane elimination via a bubble oxygenator during extracorporeal circulation.

It has been suggested that inhalational anesthetics should be discontinued at least 15 minutes prior to termination of extracorporeal circulation (ECC) to avoid myocardial depression. However, data regarding elimination of inhalation agents via a bubble oxygenator from hypothermic, hemodiluted patients have not been previously reported. The washout of isoflurane (ISF) from ten cardiac surgical patients using mass spectrometry was studied. The mean baseline oxygenator exhaust concentration of ISF was 0.85% prior to termination of ECC. Oxygenator concentration of ISF decreased to less than 0.05% in 8.8 +/- 2.5 minutes. Eight of ten patients had ISF washout curves best characterized by a one-compartment model, with a mean time constant of 1.94 minutes. Therefore, 95% washout of ISF should occur in 5.8 minutes (three time constants). It is suggested that ISF may be used closer to the termination of ECC than previously recommended without fear of significant myocardial depression.

Aged↗
PubMed1987

Pulmonary oedema following airway obstruction in a patient with Hodgkin's disease.

We report a case of pulmonary oedema following airway obstruction in a patient who underwent biopsy of a tumour involving the anterior mediastinum and neck. The occurrence of airway obstruction in patients with anterior mediastinal masses, and the pathogenesis of pulmonary oedema occurring in association with airway obstruction, are discussed.

Adult↗