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Biomedical subjects

U Norinder

Publications and source records attributed to U Norinder.

At least 19 recordsLinked to original sources
PubMed2001

Experimental and computational screening models for the prediction of intestinal drug absorption.

The aim of this study was to devise experimental protocols and computational models for the prediction of intestinal drug permeability. Both the required experimental and computational effort and the accuracy and quality of the resulting predictions were considered. In vitro intestinal Caco-2 cell monolayer permeabilities were determined both in a highly accurate experimental setting (Pc) and in a faster, but less accurate, mode (Papp). Computational models were built using four different principles for generation of molecular descriptors (atom counts, molecular mechanics calculations, fragmental, and quantum mechanics approaches) and were evaluated for their ability to predict intestinal membrane permeability. A theoretical deconvolution of the polar molecular surface area (PSA) was also performed to facilitate the interpretation of this composite descriptor and allow the calculation of PSA in a simplified and fast mode. The results indicate that it is possible to predict intestinal drug permeability from rather simple models with little or no loss of accuracy. A new, fast computational model, based on partitioned molecular surface areas, that predicts intestinal drug permeability with an accuracy comparable to that of time-consuming quantum mechanics calculations is presented.

Biological Transport↗
PubMed2001

Theoretical calculation and prediction of drug transport processes using simple parameters and partial least squares projections to latent structures (PLS) statistics. The use of electrotopological state indices.

A method of modeling and predicting drug transport processes using simple, theoretically computed molecular descriptors and multivariate statistics has been investigated in four data sets related to Caco-2 cell permeability, human intestinal absorption, brain-blood partitioning, and immobilized artificial membrane (IAM) chromatography. The program Molconn-Z was used to compute theoretical molecular descriptors related to electrotopological state indices. Additional parameters related to size and lipophilicity [i.e., calculated molar refraction (CMR) and octanol-water partition coefficient (CLOGP)] were also used in the statistical modeling. Good statistical models were derived (r(2) and Q(2) values ranged from 0.75 to 0.93 and 0.70 to 0.89, respectively) that permit fast computational (electronic) screening and prioritization of virtual libraries.

Blood-Brain Barrier↗
PubMed2001

Prediction of drug transport processes using simple parameters and PLS statistics. The use of ACD/logP and ACD/ChemSketch descriptors.

A method of modelling and predicting biopharmaceutical properties using simple theoretically computed molecular descriptors and multivariate statistics has been investigated for several data sets related to solubility, IAM chromatography, permeability across Caco-2 cell monolayers, human intestinal perfusion, brain-blood partitioning, and P-glycoprotein ATPase activity. The molecular descriptors (e.g. molar refractivity, molar volume, index of refraction, surface tension and density) and logP were computed with ACD/ChemSketch and ACD/logP, respectively. Good statistical models were derived that permit simple computational prediction of biopharmaceutical properties. All final models derived had R(2) values ranging from 0.73 to 0.95 and Q(2) values ranging from 0.69 to 0.86. The RMSEP values for the external test sets ranged from 0.24 to 0.85 (log scale).

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Theoretical calculation and prediction of P-glycoprotein-interacting drugs using MolSurf parametrization and PLS statistics.

A method for the modelling and prediction of P-glycoprotein-associated ATPase activity using theoretically computed molecular descriptors and multivariate statistics has been investigated using 22 diverse drug-like compounds. The program MolSurf was used to compute theoretical molecular descriptors related to physicochemical properties such as lipophilicity, polarity, polarizability and hydrogen bonding. The multivariate partial least squares projections to latent structures (PLS) method was used to delineate the relationship between the P-glycoprotein-associated ATPase activity and the theoretically computed molecular descriptors. The PLS analysis of the entire data set, with the exclusion of tamoxifen, resulted in one significant PLS component according to cross-validation with R(2)=0.718, Q(2)=0. 695, S.D.=0.475, F=48.37, RMSE(tr)=0.452, p<0.001. Properties associated with the size of the molecular surface, polarizability and hydrogen bonding had the largest impact on the P-glycoprotein-associated ATPase activity. All these properties should be high to promote high ATPase activity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Refinement of Catalyst hypotheses using simplex optimisation.

The program HypoOpt in combination with the MSI program citest has been used to optimise and expand 3D QSAR Catalyst hypotheses using simplex optimisation coupled with cross-validation. Three data sets related to angiotensin converting enzyme inhibition, squalene epoxidase inhibition and HIV protease inhibition were used to investigate the outcome of hypothesis optimisation. Simplex optimisation using leave-one-out cross-validation during the hypothesis refinement resulted in improved models with respect to predictivity of an external test set. Furthermore, the utilisation of the geometry of the active site for the HIV protease inhibitors, represented by Catalyst 'excluded volume' features, resulted in an optimised hypothesis with improved predictivity compared with the corresponding hypothesis derived without receptor information.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Beat-to-beat QRS amplitude variability in elite endurance athletes.

Results from variance electrocardiography, displaying the wide-band, phase-locked electrical micro-variability during the depolarization phase, was analysed versus clinical data, echocardiographic structural and functional variables and myocardial scintigraphic findings in 174 elite orienteers compared with 37 age-matched elite endurance athletes and 50 age-matched, healthy medical students. PCA analysis identified a subgroup of five orienteers deviating from the rest of the study group and both control groups with regard to their QRS amplitude variability. No correlations were found between pathology by medical history or any of the echocardiographic and scintigraphic variables or by the variance electrocardiographic aberrations in any of the groups studied.

Adolescent↗
PubMed1999

Theoretical calculation and prediction of intestinal absorption of drugs in humans using MolSurf parametrization and PLS statistics.

A method for modeling and prediction of the intestinal absorption of drugs in humans using theoretically computed molecular descriptors and multivariate statistics has been investigated using 20 diverse drug-like compounds. The program MolSurf was used to compute theoretical molecular descriptors related to physicochemical properties such as lipophilicity, polarity, polarizability and hydrogen bonding. The multivariate Partial Least Squares Projections to Latent Structures (PLS) method was used to delineate the relationship between the intestinal absorption of drugs in humans and the theoretically computed molecular descriptors.Good statistical models were derived. Properties associated with hydrogen bonding had the largest impact on absorption and should be kept to a minimum to promote high absorption. High charge-transfer properties and the presence of surface electrons, i.e. valence electrons, which are not tightly bonded to the molecule, were also found to promote high absorption.

Computer Simulation↗
PubMed1998

Theoretical calculation and prediction of brain-blood partitioning of organic solutes using MolSurf parametrization and PLS statistics.

Sixty-three structurally diverse compounds were investigated to statistically model the brain-blood partitioning of organic solutes using theoretically computed molecular descriptors and multivariate statistics. The program MolSurf was used to compute theoretical molecular descriptors related to physicochemical properties such as lipophilicity, polarity, polarizability, and hydrogen bonding. The multivariate Partial Least Squares Projections to Latent Structures (PLS) method was used to delineate the relationship between the brain-blood partitioning of organic solutes and the theoretically computed molecular descriptors. Good statistical models were derived. Properties associated with polarity and Lewis base strength had the largest impact on the blood-brain partitioning and should be kept to a minimum to promote high partitioning. The absence of atoms capable of hydrogen bonding interactions as well as high lipophilicity and the presence of polarizable surface electrons, i.e., valence electrons, were also found to promote high brain-blood partitioning. The results indicate that theoretically computed molecular MolSurf descriptors in conjunction with multivariate statistics of PLS type can be used to successfully model the brain-blood partitioning of organic solutes and hence differentiate drugs with poor partitioning from those with acceptable partitioning at an early stage of the preclinical drug-discovery process.

Blood-Brain Barrier↗
PubMed1997

Theoretical calculation and prediction of Caco-2 cell permeability using MolSurf parametrization and PLS statistics.

PURPOSE: To statistically model the permeability across Caco-2 cell monolayers using theoretically computed molecular descriptors and multivariate statistics. METHODS: Seventeen structurally diverse compounds were investigated. The program MolSurf was used to compute theoretical molecular descriptors related to physico-chemical properties such as lipophilicity, polarity, polarizability and hydrogen bonding. The multivariate Partial Least Squares Projections to Latent Structures (PLS) method was used to delineate the relationship between the permeability across Caco-2 cell monolayers and the theoretically computed molecular descriptors. RESULTS: Excellent statistical models were derived. Properties associated with hydrogen bonding had the largest impact on diffusion through the monolayers and should be kept at a minimum to promote high permeability. High lipophilicity and the presence of surface electrons, i.e. valence electrons, which are not tightly bonded to the molecule, were also found to have a favorable influence to achieve high permeability. CONCLUSIONS: The results indicate that theoretically computed molecular MolSurf descriptors in conjunction with multivariate statistics of PLS type can be used to successfully model permeability across Caco-2 cell monolayers and, thus, differentiate drugs with poor permeability from those with acceptable permeability at an early stage of the preclinical drug discovery process.

Caco-2 Cells↗
PubMed1997

A quantitative structure-activity relationship study of some substance P-related peptides. A multivariate approach using PLS and variable selection.

Nine new analogues of substance P (SP) were designed using quantitative sequence-activity models based on the amino acid z-scales with PLS as the statistical method and the GOLPE procedure for variable selection. The nine SP analogues were synthesised by solid-phase peptide synthesis and tested for affinity to the NK-1 receptor from rat brain with radio receptor assay using [125I]-Bolton-Hunter substance P as labelled ligand. All of the new substance P analogues showed high affinities, with IC50 values of less than 0.8 nM. One analog, Lys-Arg-Ala-Lys-Phe-Met-Met-Phe-Phe-Gly-Leu-Let-NH2, showed a exceptional high affinity for the NK1 receptor, with IC50 = 5 pM.

Animals↗
PubMed1992

Determinants for DNA-binding site recognition by the glucocorticoid receptor.

The glucocorticoid receptor binds with high specificity to glucocorticoid response elements, discriminating them from other closely related binding sites. Three amino acids in the recognition alpha-helix of the DNA-binding domain of the receptor are primarily responsible for this specific DNA binding activity. In this study we analyze in detail how these residues determine the specific DNA binding by studying a series of mutant glucocorticoid receptor DNA-binding domains containing all combinations of glucocorticoid and estrogen receptor-specific residues at these positions. Statistical analysis of the results enables us to create models describing the association between amino acids and base pairs. Several strategies appear to be used in accomplishing discrimination between the glucocorticoid and estrogen response elements. Single residues (i.e., Val-443 in the glucocorticoid receptor and Glu-439 in the estrogen receptor) appear to form both positive contacts with specific base pairs in the cognate binding site and negative contacts in the non-cognate site. In the glucocorticoid receptor Ser-440 is pleiotropically negative for all sites tested but the negative effect is stronger for the estrogen response element thus contributing to binding site discrimination. Furthermore, combinations of amino acids appear to act synergistically, most often causing a reduction in binding to non-cognate sites.

Amino Acid Sequence↗
PubMed1992

Inhibition of [3H]paroxetine binding by various serotonin uptake inhibitors: structure-activity relationships.

Fifty-four compounds structurally related to zimeldine or alaproclate and eight reference substances were examined as inhibitors of the high affinity binding of [3H]paroxetine to rat cerebral cortical membranes as a measure of the affinity of the 5-hydroxytryptamine (5-HT) transporter. None of the compounds had an affinity as high as paroxetine (KD = 0.026 nM). The most potent compound, 3-(4-methoxyphenyl)-1-methyl-3-phenylpropylamine (2) had a 5 times lower affinity than paroxetine. Some other diphenyl-1-methyl-propylamines displayed high affinity, e.g. the 4-bromo (4) and 2-bromo (7) derivatives. The primary amine analogue of zimeldine substituted with an alpha-methyl group (19) had an affinity only slightly less than that of norzimeldine (11) but an almost 100 times higher affinity than that of the unsubstituted primary zimeldine analogue (57). These observations indicate that a methyl group on the alpha-carbon and on the nitrogen both increase the affinity for the [3H]paroxetine binding site. The structure activity relationship for the compounds to inhibit [3H]paroxetine binding was highly significantly correlated to the inhibition of 5-HT uptake in mouse brain slices (P less than 0.01) and to the inhibition of noradrenaline uptake in the same slices (P less than 0.05). QSAR analysis of the zimeldine series of compounds indicates that substitution of halogens of the 2-position of the phenyl ring is unfavourable. The cis configuration promotes higher activity than the trans configuration.

Animals↗
PubMed1992

Experimental design-based quantitative structure-toxicity relationship of some local anaesthetics using the PLS method.

A quantitative structure-toxicology (LD50) relationship for some N-alkylsuccinimides is presented. The relationship is based on a small and carefully selected training set using experimental design methodology. The good predictability, an overall r2 value of 0.75, with such an approach is demonstrated. Factors such as large N-alkyl groups, substitution in the aromatic ring and a long side chain between the two nitrogens are favourable for low toxicity.

Least-Squares Analysis↗
PubMed1992

PLS-based quantitative structure-activity relationship for substituted benzamides of clebopride type. Application of experimental design in drug design.

The advantageous approach of using an experimentally designed training set as the basis for establishing a quantitative structure-activity relationship with good predictive capability is described. The training set was selected from a fractional factorial design scheme based on a principal component description of physico-chemical parameters of aromatic substituents. The derived model successfully predicts the activities of additional substituted benzamides of 6-methoxy-N-(4-piperidyl)salicylamide type. The major influence on activity of the 3-substituent is demonstrated.

Benzamides↗
PubMed1992

A quantitative structure-activity relationship for some dopamine D2 antagonists of benzamide type.

A quantitative structure-activity relationship (QSAR) for some 6-methoxybenzamides having 1-ethyl-2-pyrrolidinylmethyl side chains with respect to the inhibition of [3H]spiperone binding is established using the PLS method. An experimental design approach to select the training set compounds is demonstrated. The established relationship between structure and in vitro activity indicates the dominating influence of the substituents in the 3-position as well as the importance of (S)-configuration in the side chain. A methoxy substituent in the 5-position is also beneficiary for high activity. Both salicylamides and non-salicylamides could be accommodated in the analysis, which supports the notion of a common binding site in the receptor.

Benzamides↗