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PubMed1997

Structural analysis of the H166G site-directed mutant of galactose-1-phosphate uridylyltransferase complexed with either UDP-glucose or UDP-galactose: detailed description of the nucleotide sugar binding site.

Galactose-1-phosphate uridylyltransferase plays a key role in galactose metabolism by catalyzing the transfer of a uridine 5'-phosphoryl group from UDP-glucose to galactose 1-phosphate. The enzyme from Escherichia coli is composed of two identical subunits. The structures of the enzyme/UDP-glucose and UDP-galactose complexes, in which the catalytic nucleophile His 166 has been replaced with a glycine residue, have been determined and refined to 1.8 A resolution by single crystal X-ray diffraction analysis. Crystals employed in the investigation belonged to the space group P2(1) with unit cell dimensions of a = 68 A, b = 58 A, c = 189 A, and beta = 100 degrees and two dimers in the asymmetric unit. The models for these enzyme/substrate complexes have demonstrated that the active site of the uridylyltransferase is formed by amino acid residues contributed from both subunits in the dimer. Those amino acid residues critically involved in sugar binding include Asn 153 and Gly 159 from the first subunit and Lys 311, Phe 312, Val 314, Tyr 316, Glu 317, and Gln 323 from the second subunit. The uridylyltransferase is able to accommodate both UDP-galactose and UDP-glucose substrates by simple movements of the side chains of Glu 317 and Gln 323 and by a change in the backbone dihedral angles of Val 314. The removal of the imidazole group at position 166 results in little structural perturbation of the polypeptide chain backbone when compared to the previously determined structure for the wild-type enzyme. Instead, the cavity created by the mutation is partially compensated for by the presence of a potassium ion and its accompanying coordination sphere. As such, the mutant protein structures presented here represent valid models for understanding substrate recognition and binding in the native galactose-1-phosphate uridylyltransferase.

Binding Sites↗

PubMed2002

Solid-phase synthesis of dysidiolide-derived protein phosphatase inhibitors.

Biologically active natural products can be regarded as evolutionary selected and biologically validated starting points in structural space for the development of compound libraries. For libraries designed and synthesized around a given natural product, a higher hit rate and the identification of biologically relevant hits can be expected, justifying a probably higher investment in the development of the corresponding syntheses. This approach requires the development of complex multistep reaction sequences on the solid phase. Employing the protein phosphatase Cdc25 inhibitor dysidiolide as an example, we demonstrate that this goal can be achieved successfully. The reaction sequences developed led to dysidiolide analogues in overall 8-12 linear steps with the longest sequence on the solid support amounting to up to 11 sequential transformations. The desired products were obtained in overall yields ranging from 6% to 27% and in multimilligram amounts starting from 100 mg of resin. The transformations applied include a variety of very different reaction types widely used in organic synthesis (i.e., an asymmetric cycloaddition employing a removable chiral auxiliary, different organometallic transformations, olefination reactions, different oxidation reactions, acidic hydrolyses, and a nucleophilic substitution). Biological investigation of the eight dysidiolide analogues synthesized showed that they inhibit Cdc25C in the low micromolar range with the IC(50) value varying by a factor of 20 and that they display considerable and differing biological activities in cytotoxicity assays employing different cancer cell lines.

4-Butyrolactone↗

PubMed2003

Development of natural product-derived receptor tyrosine kinase inhibitors based on conservation of protein domain fold.

Receptor tyrosine kinases (RTKs) such as Tie-2, IGF1R, Her-2/Neu, EGFR, and VEGFR1-3 play crucial roles in the control of cell growth and differentiation. Inhibition of such RTKs has become a major focus of current anticancer drug development, and therefore the discovery of new classes of inhibitors for these signal-transducing proteins is of prime importance. We have recently proposed a novel concept for improving the hit-finding process by employing natural products as biologically validated starting points in structural space for compound library development. In this concept, natural products are regarded as evolutionary chosen ligands for protein domains which are structurally conserved yet genetically mobile. Here we report on the discovery of novel and highly selective VEGFR-2 and -3, Tie-2, and IGF1R inhibitors derived from the naturally occurring Her-2/Neu kinase inhibitor nakijiquinone C and developed on the basis of this concept. Based on the structure of the natural product, a small library (74 members) was synthesized and investigated for inhibition of kinases with highly similar ATP-binding domains. The library yielded inhibitors with IC(50)s in the low micromolar range with high frequency (7 out of 74). In particular, four inhibitors of Tie-2 were found, a kinase critically involved in the formation of new blood vessels from preexisting ones (angiogenesis) and believed to be a new promising target in antitumor therapy. These results support the "domain concept". To advance the development of improved inhibitors, extensive molecular modeling studies were undertaken, including the construction of new homology models for VEGFR-2 and Tie-2. These studies revealed residues in the kinase structure which are crucial to the development of tailor-made receptor tyrosine kinase inhibitors.

Amino Acid Sequence↗

PubMed2005

Conformation mining: an algorithm for finding biologically relevant conformations.

Discovering essential features shared by active compounds, an important step in drug-design, is complicated by conformational flexibility. We present a new algorithm to efficiently mine the conformational space of multiple actives and find small subsets of conformations likely to be biologically relevant. The approach identifies chemical and steric similarities between actives, providing insight into features important for binding when structural data are absent. Validation studies (thrombin and CDK2 data) produce alignments similar to protein-based alignments.

Algorithms↗

PubMed2004

Competitive adsorption of aqueous metal ions on an oxidized nanoporous activated carbon.

Competitive adsorption is the usual situation in real applications, and it is of critical importance in determining the overall performance of an adsorbent. In this study, the competitive adsorption characteristics of all the combinations of binary mixtures of aqueous metal ion species Ca2+(aq), Cd2+(aq), Pb2+(aq), and Hg2+(aq) on a functionalized activated carbon were investigated. The porous structure of the functionalized active carbon was characterized using N2 (77 K) and CO2 (273 K) adsorption. The surface group characteristics were examined by temperature-programmed desorption, Fourier transform infrared spectroscopy, Raman spectroscopy, acid/base titrations, and measurement of the point of zero charge (pHpzc). The adsorption of aqueous metal ion species, M2+(aq), on acidic oxygen functional group sites mainly involves an ion exchange mechanism. The ratios of protons displaced to the amount of M2+(aq) metal species adsorbed have a linear relationship for both single-ion and binary mixtures of these species. Hydrolysis of metal species in solution may affect the adsorption, and this is the case for adsorption of Hg2+(aq) and Pb2+(aq). Competitive adsorption decreases the amounts of individual metal ions adsorbed, but the maximum amounts adsorbed still follow the order Hg2+(aq) > Pb2+(aq) > Cd2+(aq) > Ca2+(aq) obtained for single metal ion adsorption. The adsorption isotherms for single metal ion species were used to develop a model for competitive adsorption in binary mixtures, involving exchange of ions in solution with surface proton sites and adsorbed metal ions, with the species having different accessibilities to the porous structure. The model was validated against the experimental data.

Journal Article↗

PubMed2001

A test of the reliability and validity of the Multnomah Community Ability Scale.

Previous research shows that the Multnomah Community Ability Scale (MCAS) total score is reliable and has predictive validity. This study evaluates the MCAS total and sub-scale scores on a sample of 1,250 outpatient mental health clients in Washington State. The MCAS sub-scales are reliable, and there is evidence for their concurrent validity. However, the factor structure of the MCAS only partially replicated the hypothesized sub-scales, and the authors recommend that sub-scales as currently constructed not be used as performance indicators. If only the total MCAS is of interest to users, the authors recommend using the single-item SOFAS rather than the 17-item MCAS.

Adolescent↗

PubMed1998

20 Questions of Gamblers Anonymous: A Psychometric Study with Population of Spain.

The authors present a psychometric study of the questionnaire proposed by the Gamblers Anonymous organization for the self-assessment of problem gambling. The study was carried out in Spain with two samples: one of 127 problem gamblers (mean age: 41.67; sex: 78.7% men; mean duration of the problem: 5 years) and the other of 142 social gamblers (mean age: 38.46; sex: 60% men). The questionnaire was self-applied, in the presence of one of the investigators in case any doubts arose. The results indicate that it is a good screening instrument, with high reliability (Cronbach's alpha = 0.94), good covergent validity (the correlation with the SOGS questionnaire is high (r = 0.94; p < 0.001)), good factorial validity (the questionnaire's structure is unidimensional and coherent (just one factor explains more than 50% of the variance)), and its discriminative power is high (diagnostic efficacy = 98.88%). The study offers a comparative analysis of this instrument with other measures of problem gambling, emphasizing its extraordinary performance.

Journal Article↗

PubMed2001

Synthesis, X-ray crystallographic structures of thio substituted N-acetyl N'-methylamide alanine and evaluation of sp sulfur parameters of the CFF91 force field.

Acetyl thioalanine N-methyl (Ac-Alat-NHMe) and thioacetyl alanine N-methyl (Act-Ala-NHMe) were synthesized, crystallized and their X-ray diffraction structures determined for the first time. Both molecules adopted beta-sheet conformations and showed similar hydrogen bonding patterns with one molecular surface forming two oxo hydrogen bonds and the other forming two thio hydrogen bonds. The crystal structure data for the two thioamides provided a validation of the thioamide parameters for the newly derived CFF91 force field because the observed crystal (phi, psi) angles were situated in the global minimum regions of the theoretical (phi, psi) map predicted using the parameters. In addition, the parameters were further validated because conformational energy minimization of the crystal structure produced low deviations in unit cell dimensions, bond lengths, bond angles and torsional angles, and a 120-ps molecular dynamics simulation also gave a low deviation for the most probable N-H...S=C bond distance.

Alanine↗

PubMed1985

Cross-cultural examination of the semantic dimensions of body postures.

In two studies, we examined the cross-cultural validity of the dimensional structures with which postures are judged. In Study 1, 686 Japanese subjects rated 40 posture expressions on sixteen 5-point semantic differential scale items. Subjects inferred an encoder's attitude towards oneself (i.e., the decoding subject) in hypothetical dyadic situations. A principal-component factor analysis yielded evidence for three independent dimensions resembling those proposed by Schlosberg (1954), Osgood (1966), and Williams and Sundene (1965). These three factors were named self-fulfillment, interpersonal positiveness, and interpersonal consciousness. In Study 2, 336 Japanese students again rated the 40 posture expressions on the sixteen 5-point differential items, but an attempt was made to control for the status of the hypothetical encoder. The results of this study essentially replicated those of Study 1. One interesting finding was that although we found the same factors as those found in studies conducted in the West, the order of the factors in our studies was the reverse of the order found in these previous studies. The findings are discussed in terms of proposed cultural differences in the maintenance of human relations.

Adolescent↗

PubMed2000

Coping with neck and low back pain in the general population.

This study had 2 objectives: (a) to assess the psychometric properties of the Pain Management Inventory (PMI; G. K. Brown & P. M. Nicassio, 1987) with individuals in the general population with neck or low back pain, and (b) to assess the relationship between pain severity and coping. Data were taken from a mailed survey of a random sample of adults residing in Saskatchewan, Canada. Results validated the 2-factor structure of the PMI and provided evidence for the internal consistency of the coping subscales. Regression analyses revealed that passive coping was associated with being married, greater pain severity, depression, and poor health. Active coping was associated with female gender, higher education, less depression, good health, and frequent exercise. This study provides psychometric data to support the use of the PMI and information about factors associated with use of active and passive coping strategies in pain sufferers.

Adaptation, Psychological↗

PubMed2004

Confirmatory factor analysis of the california verbal learning test in patients with epilepsy: relationship to clinical and neuropathological markers of temporal lobe epilepsy.

Latent constructs involved in California Verbal Learning Test (D. C. Delis, J. H. Kramer, E. Kaplan, & B. A. Ober, 1987) performance were examined using confirmatory factor analysis in 388 epilepsy surgery candidates. Eight factor models were compared. A single-factor model was examined, along with 7 models accommodating constructs of auditory attention, inaccurate recall, and delayed recall in different combinations. The retained model consisted of 3 correlated factors: Auditory Attention. Verbal Learning, and Inaccurate Recall. Validity of this factor structure was examined in a subsample of patients with left and right temporal lobe epilepsy. All 3 factors were related to seizure focus and magnetic resonance imaging hippocampal volume. Only Verbal Learning was related to hippocampal neuropathology, supporting the distinction between learning and attention in the factor structure.

Adolescent↗

PubMed2005

Probing the structure of Saccharomyces cerevisiae RNase MRP.

In yeast, RNase MRP (mitochondrial RNA processing), a ribonucleoprotein precursor rRNA processing enzyme, possesses one putatively catalytic RNA and ten protein subunits and is highly related to RNase P. Structural analysis of the MRP RNA provides data that closely match a previous secondary-structure model derived from phylogenetic analysis, with the exception of an additional stem. This stem occupies an equivalent position to the P7 stem of RNase P RNA and its inclusion confers on MRP RNA a greater similarity to the core P RNA structure. In vivo studies indicate that the P7-like stem can form, but is not a part of, the active enzyme structure. Stem formation would increase RNA stability in the absence of proteins and our alternative structure may be a valid intermediate species in RNase MRP assembly. Further ongoing studies of this enzyme reveal an extensive network of interactions between subunits and a probable central role for the Pop1, Pop4 and Pop7 subunits.

Base Pairing↗

PubMed2000

The development of an instrument to measure the compliance of adolescents with a chronic disease.

The purpose of this paper was to describe the process of developing an instrument for measuring the compliance of adolescents with a chronic disease. The aim was to develop an instrument that could be used in a clinical setting to evaluate the compliance of young people with a chronic disease and to test a theoretical model of compliance, which had been developed along with the instrument. The instrument was originally developed to measure the compliance of adolescents with diabetes and later adjusted to measure the compliance of adolescents with asthma, rheumatoid arthritis and epilepsy. To test and develop the instrument, face and criterion validity, factor analyses, linear structural relations (LISREL) analyses, correlation coefficients and Cronbach's alpha were used. The instrument has 13 background questions and 41 items to measure compliance and factors connected to it.

Adolescent↗

PubMed1999

Conformations in solution of the fuscopeptins. Phytotoxic metabolites of Pseudomonas fuscovaginae.

Fuscopeptins are phytotoxic amphiphilic lipodepsipeptides containing 19 amino acid residues. They are produced by the plant pathogenic bacterium Pseudomonas fuscovaginae in two forms, A and B, which differ only in the number of methylene groups in the fatty acid chain. Their covalent structure and biological properties have been reported previously. CD and NMR spectroscopy investigations in solution revealed the absence of identifiable elements of secondary and tertiary structure for these molecules. Fuscopeptin B appears to be completely unstructured in aqueous solution, and has a large molecular flexibility. A dramatic conformational change was observed upon addition of trifluoroethanol. This study reports the complete interpretation of the two-dimensional NMR spectra and the NOE results obtained for fuscopeptin B in water/trifluoroethanol solutions; the signals relative to the peptidic moiety are identical to those observed for fuscopeptin A. The results of this investigation were used to determine the solution structure of fuscopeptin B by computer simulations applying distance geometry and simulated annealing procedures. In water/trifluoroethanol solutions the peptidic region appears to have a partly helical structure. The lactonic ring assumes defined conformations very similar to those already reported for other lipodepsipeptides. The structure for fuscopeptin B in solution is also valid for fuscopeptin A because of the negligible structural difference between the two metabolites.

Amino Acid Sequence↗

PubMed2004

[Outcome quality of psychosomatic rehabilitation: goal attainment scaling on the basis of a structured catalogue of therapy goals].

Within the scope of a multicenter study regarding the outcome quality of inpatient psychosomatic rehabilitation a structured catalogue of therapy goals (SZK, strukturierter Therapiezielkatalog) was developed. The catalogue contains 89 predetermined therapy goals as well as the option to formulate further goals in own words. The SZK is available both as a patient and as a therapist version. At the beginning of treatment up to five primary objectives are chosen from the list. At the end of treatment and at the 1-year follow-up the level of achievement of objectives is assessed. Moreover the SZK contains the option to mark goals as not relevant any more and to add goals which came up during the treatment and to evaluate them regarding the level of achievement. The study on hand asks for empirical identification of the target structure. Furthermore, reliability and validity of the calculated measures of goal attainment are analysed. As the most important finding the SZK turns out to be a practical and economical assessment instrument for goal-oriented evaluation.

Adult↗

PubMed2004

Generic low-molecular-weight heparins: some practical considerations.

It is now widely accepted that various low-molecular-weight heparins (LMWHs) exhibit specific molecular and structural attributes that are determined by the type of manufacturing process used. For example, enoxaparin, which is prepared by benzylation followed by alkaline hydrolysis of unfractionated heparin (UFH), exhibits a double bond at the nonreducing end and the presence of a unique bicyclic structure namely 1,6 anhydromanno glucose or mannose, or both, at the reducing end. Similarly, the other LMWHs, such as dalteparin, nadroparin, tinzaparin, and parnaparin, exhibit specific structural characteristics that may contribute to their own unique biochemical and pharmacological profiles. These unique features may not exhibit any major influence on the routinely determined anti-Xa and anti-IIa activities. However, these may have an impact on the pharmacokinetics and other biological actions such as the interactions with growth factors, blood components, and vascular cells. This is the reason for the initial caution for the noninterchangeability of the anti-Xa adjusted dosing of the different LMWHs. Although the nonanticoagulant biological effects of these drugs are poorly understood at this time, they are now recognized as contributing significantly to the overall therapeutic effects of these drugs. Because some of these drugs have proved to be effective in the management of cancer-associated thrombosis and exhibit improvements in mortality outcome, these LMWHs may also produce several other effects by modulating inflammatory processes, apoptosis, and other regulatory functions related to cellular functions at different levels. Thus, the interactions of these LMWHs with antithrombin and heparin cofactor II are not the only determinants of their biological actions. Release of tissue factor pathway inhibitor (TFPI), regulation of cytokines, nitric oxide, and eicosanoids contribute to their individuality. Such properties are not only dependent on the oligosaccharide sequence and consensus sites but also depend mainly on microchemical and structural attributes in these drugs. European Pharmacopoeia (EP) and the World Health Organization (WHO) have developed guidelines to characterize these agents in terms of their molecular and biological profile. Regulatory agencies such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMEA) consider each of these drugs as distinct pharmacological agents. This has prompted the requirement for product-specific clinical data for the approval of their use in various clinical indications. There is a clear concern regarding the development of potential generic versions of branded products and the submissions by generic manufacturers for the regulatory approval of generic interchangeability that refers to the substitution of an apparent chemically identical and bioequivalent versions of the branded LMWHs. Currently, there are no regulatory guidelines or consensus opinions on the acceptance of generic versions of the branded products. Because the LMWHs represent not only a biological entity but also product-specific molecular and structural attributes, the acceptance of a generic version must be based on clearly defined guidelines stipulating minimal molecular and structural, biological, and clinical validation requirements. It is therefore to be stressed that each of the LMWHs is a distinct drug entity that characteristically exhibits a product-based therapeutic spectrum in different thrombotic and nonthrombotic disorders. Thus, until the establishment of valid regulatory guidelines for the generic interchangeability of the commercially available LMWHs is completed, generic substitutes are not recommended.

Anticoagulants↗

PubMed1993

[Prevention of human birth trauma I. Computer-assisted simulation of delivery using magnetic resonance tomography and finite element analysis].

Imaging procedures suitable for diagnosis of cephalopelvic disproportion, such as radiological pelvimetry, computer- or magnetic resonance imaging (MRI) fail to reflect the dynamics of delivery, including deformations of the birth channel as well as of foetal structures. In order to validate findings of imaging procedures in this respect, a method has been developed to perform dynamic, biomechanical postprocessing of the static information obtained from MRI. Using a specially developed software MRI pixel, matrices of the maternal pelvis and the foetal head were colour-coded and--according to the principle of equal density--line data were created. After sectional attribution of the resulting polygones, a three-dimensional mesh of so called Finite Elements (FE) was created, which can then be used for deformation analysis. The foetal head was then moved through the birth channel by means of computed simulation. This allows not only ongoing deformations to be visualised, but also resulting forces can be calculated at any time of the delivery process for any point of the anatomical model. Furthermore, these calculations can be performed assuming various conditions such as different cephalopelvic dimensions and various labour forces or biomechanical properties of the tissues involved. This paper aims at presenting the method and its mode of working by means of one example of a computed birth simulation.

Adult↗

PubMed2006

A QUICKSTEP-based quantum mechanics/molecular mechanics approach for silica.

Quantum mechanics/molecular mechanics (QM/MM) approaches are currently used to describe several properties of silica-based systems, which are local in nature and require a quantum description of only a small number of atoms around the site of interest, e.g., local chemical reactivity or spectroscopic properties of point defects. We present a QM/MM scheme for silica suitable to be implemented in the general QM/MM framework recently developed for large scale molecular dynamics simulations, within the QUICKSTEP approach to the description of the quantum region. Our scheme has been validated by computing the structural and dynamical properties of an oxygen vacancy in alpha-quartz, a prototypical defect in silica. We have found that good convergence in the Si-Si bond length and formation energy is achieved by using a quantum cluster of only eight atoms in size. We check the suitability of the method for molecular dynamics and evaluate the Si-Si bond frequency from the velocity-velocity correlation function.

Journal Article↗