PubMed Health⌕ Search

Biomedical subjects

F S Jørgensen

Publications and source records attributed to F S Jørgensen.

At least 19 recordsLinked to original sources
PubMed2001

A new concept for multidimensional selection of ligand conformations (MultiSelect) and multidimensional scoring (MultiScore) of protein-ligand binding affinities.

In this work, eight different scoring functions have been combined with the aim of improving the prediction of protein-ligand binding conformations and affinities. The obtained scores were analyzed using multivariate statistical methods to generate expressions, with the ability (1) to select the best candidate between different docked conformations of an inhibitor (MultiSelect) and (2) to quantify the protein-ligand binding affinity (MultiScore). By use of the docking program GOLD, 40 different inhibitors were docked into the active site of three matrix metalloproteinases (MMP's), yielding a total of 120 enzyme-inhibitor complexes. For each complex, a single conformation of the inhibitor was selected using principal component analysis (PCA) for the scores obtained by the eight functions SCORE, LUDI, GRID, PMF_Score, D_Score, G_Score, ChemScore, and F_Score. Binding affinities were estimated based on partial least-squares projections onto latent structures (PLS) on the eight scores of each selected inhibitor conformation. By use of this procedure, R(2) = 0.78 and Q(2) = 0.78 were obtained when comparing experimental and calculated binding affinities. MultiSelect was evaluated by applying the same method for selecting docked conformations for 18 different protein-ligand complexes of known three-dimensional structure. In all cases, the selected ligand conformations were found to be very similar to the experimentally determined ligand conformations. A more general evaluation of MultiScore was performed using a set of 120 different protein-ligand complexes for which both the three-dimensional structures and the binding affinities were known. This approach allowed an evaluation of MultiScore independently of MultiSelect. The generality of the method was verified by obtaining R(2) = 0.68 and Q(2) = 0.67, when comparing calculated and experimental binding affinities for the 120 X-ray structures. In all cases, LUDI, SCORE, GRID, and F_Score were included as important functions, whereas the fifth function was PMF_Score and ChemScore for the MMP and X-ray models, respectively.

Crystallography, X-Ray↗
PubMed2000

Structural differences of matrix metalloproteinases. Homology modeling and energy minimization of enzyme-substrate complexes.

Matrix metalloproteinases are extracellular enzymes taking part in the remodeling of extracellular matrix. The structures of the catalytic domain of MMP1, MMP3, MMP7 and MMP8 are known, but structures of enzymes belonging to this family still remain to be determined. A general approach to the homology modeling of matrix metalloproteinases, exemplified by the modeling of MMP2, MMP9, MMP12 and MMP14 is described. The models were refined using an energy minimization procedure developed for matrix metalloproteinases. This procedure includes incorporation of parameters for zinc and calcium ions in the AMBER 4.1 force field, applying a non-bonded approach and a full ion charge representation. Energy minimization of the apoenzymes yielded structures with distorted active sites, while reliable three-dimensional structures of the enzymes containing a substrate in active site were obtained. The structural differences between the eight enzyme-substrate complexes were studied with particular emphasis on the active site, and possible sites for obtaining selectivity among the MMP's are discussed. Differences in the P1' pocket are well-documented and have been extensively exploited in inhibitor design. The present work indicates that selectivity could be further improved by considering the P2 pocket as well.

Amino Acid Sequence↗
PubMed1999

Towards an understanding of drug resistance in malaria: three-dimensional structure of Plasmodium falciparum dihydrofolate reductase by homology building.

A three-dimensional (3-D) model of dihydrofolate reductase (DHFR) from Plasmodium falciparum has been constructed by homology building. The model building has been based on a structural alignment of five X-ray structures of DHFR from different species. The 3-D model of the plasmodial DHFR was obtained by amino acid substitution in the human DHFR, which was chosen as template, modification of four loops (two insertions, two deletions) and subsequent energy minimization. The active site of P. falciparum DHFR was analyzed and compared to human DHFR with respect to sequence variations and structural differences. Based on this analysis the molecular consequences of point mutations known to be involved in drug resistance were discussed. The significance of the most important point mutation causing resistance, S108N, could be explained by the model, whereas the point mutations associated with enhanced resistance, N51I and C59R, seem to have a more indirect effect on inhibitor binding.

Amino Acid Sequence↗
PubMed1999

Epidemiological studies of obstetric ultrasound examinations in Denmark 1989-1990 versus 1994-1995.

BACKGROUND: The purpose of the study was to describe number, type, time and place for all obstetric ultrasound examinations that pregnant women in Denmark had performed during their pregnancies. Further, to compare these results with results from a similar national survey performed five years previously. METHODS: During a two-week period in February 1990 and a two-week period in May 1995, all delivery departments in Denmark (1990: 57/1995: 49) participated in two identical designed studies with the aim as described above. For all women who delivered in these periods variables were recorded from the women's case records and after interview. After the exclusion of 108/145 women without complete registrations, the material consisted of 2268/2315 women; approximately 3.7%/3.4% of all deliveries in Denmark 1990/1995. The chi2 and t-test were used for statistical analyses with a statistical significance level of 5%. RESULTS: Of all obstetric ultrasound examinations 99%/96% took place in hospitals. Twenty/seven percent of the women had no examination during their pregnancies. The mean number of obstetric ultrasound examinations was 1.5/1.9 for all women and 1.9/2.1 for women who had at least one examination. In total 40%/54% of the women were offered a screening examination. Women with an offer of screening had a mean number of examinations: 1.8/2.0 and women without an offer: 1.3/1.9 (1990: p<0.05; 1995: non-significant). CONCLUSION: The studies have shown an increasing number of women with an offer of ultrasound screening and in general an increased use of ultrasound examinations in obstetrics during the five year period 1990-1995 in Denmark.

Adult↗
PubMed1999

MULTISCAN--a Scandinavian multicenter second trimester obstetric ultrasound and serum screening study.

AIM: To study the detection rates of second trimester ultrasound screening for neural tube defects (NTD), abdominal wall defects (AWD) and Down's syndrome (DS) in low risk populations at tertiary centers, and to compare the ultrasound screening detection rates with those that were obtainable by biochemical serum screening (double test: alpha-fetoprotein/human chorion gonadotrophin/age test). STUDY DESIGN: Prospective multicenter study with a three year inclusion period: 1/1/1989-31/12/1991. SUBJECTS: 27,844 low-risk women at 18-34 years of age who had a second trimester ultrasound screening examination. Of these, 10,264 also had a serum test. METHODS: An ultrasound malformation scan and a serum test were carried out at 17-19 weeks of gestation. Risk calculations regarding DS were based on alpha-fetoprotein, human chorion gonadotrophin and maternal age; performed retrospectively for the first two years. RESULTS: In total 73 cases were identified in the study population: NTD (n=34), AWD (n=7) and DS (n=32). The detection rates, (%, with 95% confidence interval) for ultrasound screening were: NTD: 79.4 (62.1-91.3); AWD: 85.7 (42.1-99.6); DS: 6.3 (0.8-20.8). In the subgroup of women who had both tests, the detection rates for ultrasound screening vs double test were: NTD: 62.5 (24.5-91.5) vs 75.0 (34.9-96.8); AWD: 66.7 (9.4-99.2) vs 100 (29.2-100.0); DS: 7.7 (0.2-36.0) vs 46.2 (19.2-74.9). The false positive rates (%) for ultrasound screening vs double test were: NTD: 0.01/3.3; AWD: 0.01/3.3; DS: 0.1/4.0. CONCLUSION: Second trimester ultrasound screening in a low risk population gave a low detection rate for fetal DS (6.3%) and an acceptable detection rate for NTD (79.4%) and AWD (85.7%). In the subgroup of women who had both tests, serum screening performed better than ultrasound as applied in the present study, especially regarding DS.

Abdominal Muscles↗
PubMed1998

[Organization of obstetric ultrasonography in Denmark 1995--description of the development since 1990].

With the aim to provide an overview of the current organisational status of obstetric ultrasound in Denmark and to describe the development since 1990, a questionnaire was sent in spring 1995 to all 49 departments responsible for the hospital antenatal care program. In addition a questionnaire was sent to the 14 imaging diagnostic departments providing ultrasound services for those of the 49 departments that had either insufficient or no ultrasound facilities. The response rate was 100. Since 1986 the National Board of Health in Denmark has recommended not to screen. At the time of the study the issue was under consideration as part of a general revision of the antenatal care program. Obstetric ultrasound was performed in 30 obstetric, 11 surgical, 12 radiological, 1 image diagnostic and 1 ultrasound department. In total approx. 140,000 obstetric ultrasound examinations were performed in 1994 in contrast to approx. 120,000 in 1989. Fifty-one point four percent of the pregnant population was routinely offered an ultrasound scan in the 10-20th week of gestation (1990: 39.9%). For 19.5% the offer included screening for foetal malformations (1990: 16.5%). In total 34 departments, responsible for the antenatal care of 86.3% of the pregnant population, wanted to continue or start giving an offer of ultrasound screening. The study documents a significant technology diffusion process of ultrasound into the specialty of obstetrics and gynaecology.

Denmark↗
PubMed1998

[Ultrasonography of pregnant women in Denmark 1994-1995--description of its development since 1989-1990].

During a two-week period in May 1995 all delivery departments in Denmark (n = 49) participated in a study with the purpose of describing number, type, time and place for all obstetric ultrasound examinations (OUL) that the women who delivered in the period had during their pregnancies. Further, the purpose was to compare the results with a similar study performed in 1990. The material consisted of 2,315 women; approximately 3.4% of all deliveries in Denmark in 1995. Of all OUL, 96% took place in hospitals. Seven percent of the women had no OUL during their pregnancies (1990: 20.3%). The mean number of OUL was 1.9 for all women and 2.1 for women who had at least one ultrasound examination. In total, 53.9% of the women were offered a screening examination (1990: 40.3%). Women with an offer of screening had a mean number of 1.96 OUL during pregnancy in contrast to 1.88 OUL for women without a screening offer (t-test, non-significant). In the subgroup of women from OB/GYN departments, women with an offer of one screening examination had a mean number of 1.94 OUL during pregnancy in contrast to 1.98 OUL for women without an offer (t-test, non-significant). In conclusion, the study has shown that in comparison with the study performed in 1990, an increasing number of women are given an offer of ultrasound screening and that there in general has been an increase in use of ultrasound examinations in obstetrics during the five-year period.

Denmark↗
PubMed1997

Substrate binding and catalytic mechanism in phospholipase C from Bacillus cereus: a molecular mechanics and molecular dynamics study.

For the first time a consistent catalytic mechanism of phospholipase C from Bacillus cereus is reported based on molecular mechanics calculations. We have identified the position of the nucleophilic water molecule, which is directly involved in the hydrolysis of the natural substrate phosphatidylcholine, in phospholipase C. This catalytically essential water molecule, after being activated by an acidic residue (Asp55), performs the nucleophilic attack on the phosphorus atom in the substrate, leading to a trigonal bipyramidal pentacoordinated intermediate (and structurally similar transition state). The subsequent collapse of the intermediate, regeneration of the enzyme, and release of the products has to involve a not yet identified second water molecule. The catalytic mechanism reported here is based on a series of molecular mechanics calculations. First, the x-ray structure of phospholipase C from B cereus including a docked substrate molecule was subjected to a stepwise molecular mechanics energy minimization. Second, the location of the nucleophilic water molecule in the active site of the fully relaxed enzyme-substrate complex was determined by evaluation of nonbonded interaction energies between the complex and a water molecule. The nucleophilic water molecule is positioned at a distance (3.8 A) from the phosphorus atom in the substrate, which is in good agreement with experimentally observed distances. Finally, the stability of the complex between phospholipase C, the substrate, and the nucleophilic water molecule was verified during a 100 ps molecular dynamics simulation. During the simulation the substrate undergoes a conformational change, but retains its localization in the active site. The contacts between the enzyme, the substrate, and the nucleophilic water molecule display some fluctuations, but remain within reasonable limits, thereby confirming the stability of the enzyme-substrate-water complex. The protocol developed for energy minimization of phospholipase C containing three zinc ions located closely together at the bottom of the active site cleft is reported in detail. In order to handle the strong electrostatic interactions in the active site realistically during energy minimization, delocalization of the charges from the three zinc ions was considered. Therefore, quantum mechanics calculations on the zinc ions and the zinc-coordinating residues were carried out prior to the molecular mechanics calculations, and two different sets of partial atomic charges (MNDO-Mulliken and AMI-ESP) were applied. After careful assignment of partial atomic charges, a complete energy minimization of the protein was carried out by a stepwise procedure without explicit solvent molecules. Energy minimization with either set of charges yielded structures, which were very similar both to the x-ray structure and to each other, although using AMI-ESP partial atomic charges and a dielectric constant of 4, yielded the best protein structure.

Bacillus cereus↗
PubMed1997

Conformational analysis of six- and twelve-membered ring compounds by molecular dynamics.

A molecular dynamics (MD)-based conformational analysis has been performed on a number of cycloalkanes in order to demonstrate the reliability and generality of MD as a tool for conformational analysis. MD simulations on cyclohexane and a series of methyl-substituted cyclohexanes were performed at temperatures between 400 and 1200 K. Depending on the simulation temperature, different types of interconversions (twist-boat-twist-boat, twist-boat-chair and chair-chair) could be observed, and the MD simulations demonstrated the expected correlation between simulation temperature and ring inversion barriers. A series of methyl-substituted 1,3-dioxanes were investigated at 1000 K, and the number of chair-chair interconversions could be quantitatively correlated to the experimentally determined ring inversion barrier. Similarly, the distribution of sampled minimum-energy conformations correlated with the energy-derived Boltzmann distribution. The macrocyclic ring system cyclododecane was subjected to an MD simulation at 1000 K and 71 different conformations could be sampled. These conformations were compared with the results of previously reported conformational analyses using stochastic search methods, and the MD method provided 19 out of the 20 most stable conformations found in the MM2 force field. Finally, the general performance of the MD method for conformational analysis is discussed.

Calorimetry↗
PubMed1997

Molecular mechanics calculations of proteins. Comparison of different energy minimization strategies.

A general strategy for performing energy minimization of proteins using the SYBYL molecular modelling program has been developed. The influence of several variables including energy minimization procedure, solvation, dielectric function and dielectric constant have been investigated in order to develop a general method, which is capable of producing high quality protein structures. Avian pancreatic polypeptide (APP) and bovine pancreatic phospholipase A2 (BP PLA2) were selected for the calculations, because high quality X-ray structures exist and because all classes of secondary structure are represented in the structures. The energy minimized structures were evaluated relative to the corresponding X-ray structures. The overall similarity was checked by calculating RMS distances for all atom positions. Backbone conformation was checked by Ramachandran plots and secondary structure elements evaluated by the length on hydrogen bonds. The dimensions of active site in BP PLA2 is very dependent on electrostatic interactions, due to the presence of the positively charged calcium ion. Thus, the distances between calcium and the calcium-coordinating groups were used as a quality index for this protein. Energy minimized structures of the trimeric PLA2 from Indian cobra (N.n.n. PLA2) were used for assessing the impact of protein-protein interactions. Based on the above mentioned criteria, it could be concluded that using the following conditions: Dielectric constant epsilon = 4 or 20; a distance dependent dielectric function and stepwise energy minimization, it is possible to reproduce X-ray structures very accurately without including explicit solvent molecules.

Algorithms↗
PubMed1996

[Attitude of pregnant women to prenatal screening].

The aim of the study was to describe the opinion of pregnant women who had accepted or declined an alpha-fetoprotein test (AFP) not only on AFP-screening in general, but also on whether every pregnant woman should be offered amniocentesis (AC)/chorion villus sampling (CVS) and an ultrasound scan for fetal malformations. An additional aim was to describe pregnant women's attitudes concerning continued research in the prenatal field. The study was performed as a questionnaire study in two regions over a one-year period from October 1, 1988 to September 30, 1989. Results are based on answers from 3331 women who had taken an AFP-test and 336 women who had declined the offer of a test. A total of 79% of the women thought that an AFP-test, 70% that an ultrasound scan for fetal malformations and 26% that AC or CVS should be offered to all pregnant women. Fifty-nine percent of the women were positive towards continued research in the prenatal field. Women who had had an AFP-test were generally much more positive towards screening and research than women who had declined, who were generally against. Women who had left school without a high school degree were on average more positive towards the screening issues than women who had this degree. In conclusion, the results obtained in this study strongly suggest that women's attitudes are very dependent on how the prenatal screening programme is already organized in their local area.

Adult↗
PubMed1995

Crystallization and preliminary X-ray analysis of a PNA-DNA complex.

Peptide nucleic acids (PNAs) are DNA mimics with a peptide backbone. PNAs are being intensely investigated owing to a potential as gene-targeted drugs. A PNA (H-GTAGATCACT-NH2)-DNA (5'-AGTGATCTAC-3') complex has been crystallized in a tetragonal space group P4(1)22 with cell dimensions a = b = 79.8, c = 99.9 angstrum. The crystals diffract to about 5 angstrum resolution.

Base Sequence↗
PubMed1995

Attitudes to prenatal screening, diagnosis and research among pregnant women who accept or decline an alpha-fetoprotein test.

The aim of the study was to describe the opinion of pregnant women who had accepted or declined an alpha-fetoprotein (AFP) test, not only on AFP screening in general, but also on whether every pregnant woman should be offered amniocentesis (AC)/chorionic villus sampling (CVS) and an ultrasound scan for fetal malformations. An additional aim was to describe pregnant women's attitudes concerning continued research in the prenatal field. The study was performed as a questionnaire study in two regions over a 1-year period from 1 October 1988 to 30 September 1989. Results are based on answers from 3331 women who had taken an AFP test and 336 women who had declined the offer of a test. A total of 79 per cent of the women thought that an AFP test, 70 per cent that an ultrasound scan for fetal malformations, and 26 per cent that AC or CVS should be offered to all pregnant women. Fifty-nine per cent of the women were positive towards continued research in the prenatal field. Women who had had an AFP test were generally much more positive towards screening and research than women who had declined, who were generally against. Women who had left school without a high school degree were on average more positive towards the screening issues that women who had this degree. In conclusion, the results obtained in this study strongly suggest that women's attitudes are very dependent on how the prenatal screening programme is already organized in their local area.

Amniocentesis↗
PubMed1995

Alpha-fetoprotein and acetylcholinesterase activity in first- and early second-trimester amniotic fluid.

Normal ranges of amniotic fluid alpha-fetoprotein (AFP) and acetylcholinesterase activity (AChE) are described for gestational weeks 11-14 using rocket gel immunoelectrophoresis for AFP quantitation and a monoclonal antibody (4F19) enzyme antigen immunoassay for AChE activity measurement. The normal ranges were established by the examination of 281 amniotic fluid samples from 281 normal pregnancies. AFP was found to increase from a median level of 14.0 MIU/l at 11 weeks to a maximum at 13 weeks (median = 18.0 MIU/l) (P < 0.05), thereafter falling (not significant). No AChE test result exceeded 4.8 nkat/l. In addition, AFP and AChE values for three cases of fetal malformation, identified by the biochemical analyses of amniotic fluid, are given. These cases included two fetuses with a neural tube defect and one fetus with an abdominal wall defect. Amniocentesis was performed at 10, 11, and 14 weeks, respectively. The AFP and AChE values were all high.

Abdominal Muscles↗
PubMed1995

Experience with early amniocentesis.

Literature concerning early genetic amniocentesis, obtained before 14-15 weeks of gestation, has been examined and compared. Key figures of post-procedural spontaneous fetal losses have been compared as well as cytogenetic data from the published series. Cytogenetically more samples fail to grow in the early weeks, but the diagnostic accuracy seems to be comparable with that of amniocentesis obtained in the later weeks. A sampling method, improving the cell yield by means of filtration, has been developed in order to lower the risk of culture failure and reduce the reporting time in the gestational weeks 11 to 13. The filter technique is under evaluation in a randomized trial. Detection of neural tube defects with early amniotic fluid sampling is possible, but whether the detection rate is comparable to that of standard amniocentesis remains to be seen. Although the safety of early amniocentesis has not yet been evaluated in a randomised study, data from almost 5,000 cases suggest that the procedure related loss rate is approximately 1%, and thus the same as for standard amniocentesis and chorionic villus sampling.

Amniocentesis↗