Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Computer Graphics”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,567 records · Page 87Linked to original sources
PubMedDate not supplied

Graph kernels for molecular structure-activity relationship analysis with support vector machines.

The support vector machine algorithm together with graph kernel functions has recently been introduced to model structure-activity relationships (SAR) of molecules from their 2D structure, without the need for explicit molecular descriptor computation. We propose two extensions to this approach with the double goal to reduce the computational burden associated with the model and to enhance its predictive accuracy: description of the molecules by a Morgan index process and definition of a second-order Markov model for random walks on 2D structures. Experiments on two mutagenicity data sets validate the proposed extensions, making this approach a possible complementary alternative to other modeling strategies.

Algorithms↗
PubMed1994

Computer modeling analysis for enediyne chromophore-apoprotein complex of macromolecular antitumor antibiotic C-1027.

On the basis of the van der Waals and electrostatic potential energy calculations and energy minimization (EM), a model for the apoprotein-chromophore complex of C-1027 has been constructed by docking the apoprotein (Apo-C1027) and the chromophore (C1027-Chr). The model of the apoprotein-chromophore complex also suggests the most probable stereochemistry of the chromophore (8R,9S,13R,17R), specific interactions between Apo-C1027 and C1027-Chr, and the origin of the stabilization of the chromophore by the apoprotein. The acetylenic bond of C1027-Chr appears to be stabilized by (1) hydrophobic interactions with the bottom of the pocket of Apo-C1027, (2) orbital interaction with Cys36-Cys45 disulfide bond, (3) van der Waals contact with Pro76, and (4) pi-pi stacking with the benzene moiety of the chromophore. In this model, molecular dynamics (MD) simulation of the chromophore indicates that the acetylene bond distance (C2-C7) of the apoprotein-bound chromophore is longer than that of the unbound chromophore.

Amino Acid Sequence↗
PubMed1993

Structure-based design of inhibitors of purine nucleoside phosphorylase. 1. 9-(arylmethyl) derivatives of 9-deazaguanine.

Purine nucleoside phosphorylase (PNP, EC 2.4.2.1) is a salvage enzyme important to the T-cell-mediated part of the immune system and as such is an important therapeutic target. This paper describes the design, synthesis, and enzymatic evaluation of potent, competitive inhibitors of PNP. Potential inhibitors were designed using the three-dimensional structure of the enzyme in an iterative process that involved interactive computer graphics to model the native enzyme and complexes of it with the inhibitors, Monte Carlo-based conformational searching, and energy minimization. Studies of the enzyme/inhibitor complexes were used to determine priorities of the synthetic efforts. The resulting compounds were then evaluated by determination of their IC50 values and by X-ray diffraction analysis using difference Fourier maps. In this manner, we have developed a series of 9-(arylmethyl)-9-deazapurines (2-amino-7-(arylmethyl)-4H-pyrrolo[3,2-d]-pyrimidin-4-ones) that are potent, membrane-permeable inhibitors of the enzyme. The IC50 values of these compounds range from 17 to 270 nM (in 1 mM phosphate), with 9-(3,4-dichlorobenzyl)-9-deazaguanine being the most potent inhibitor. X-ray analysis explained the role of the aryl groups and revealed the rearrangement of hydrogen bonds in the binding of the 9-deazaguanines in the active site of PNP relative to the binding of the 8-aminoguanines that results in more potent inhibition of the enzyme.

Animals↗
PubMed1991

A 3-D model for 5-HT1A-receptor agonists based on stereoselective methyl-substituted and conformationally restricted analogues of 8-hydroxy-2-(dipropylamino)tetralin.

The enantiomers of cis- and trans-1,2,3,4,4a,5,10,10a-octahydro-9-hydroxy-1- propylbenzo[g]quinolines (10 and 11, respectively) and the enantiomers of trans-1,2,3,4,4a,5,6,10b-octahydro-10- hydroxy-4-propylbenzo[f]quinoline (12) have been synthesized and their stereochemical and conformational characteristics have been studied by use of X-ray crystallography and molecular mechanics (MMP2) calculations. The compounds, which are conformationally restricted analogues of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2- (dipropylamino)tetralin (8-OH-DPAT; 1) have been evaluated for central 5-HT and dopamine receptor stimulating activity by use of biochemical and behavioral tests in rats. In addition, we have evaluated the ability of these compounds and a number of previously reported analogues to displace [3H]-8-OH-DPAT from 5-HT1A-binding sites. The enantiomers of 12 behave as potent 5-HT1A-receptor agonists, whereas the octahydrobenzo[g]quinoline derivatives are much less potent or inactive. In general, the affinities of the compounds correlate well with their agonist potencies. The set of compounds under study is accommodated by a novel computer-graphics-derived model for 5-HT1A-receptor agonism. The model consists of a flexible pharmacophore and a partial receptor-excluded volume.

Animals↗
PubMed1989

2-Arylindenes and 2-arylindenones: molecular structures and considerations in the binding orientation of unsymmetrical nonsteroidal ligands to the estrogen receptor.

We have studied how 2-arylindene systems, unsymmetrical nonsteroidal estrogens, orient themselves within the binding site of the estrogen receptor, relative to estradiol, by making a comprehensive comparison of the binding affinity of 16 analogues. These analogues are representatives of two major classes, those substituted at C-3 with an ethyl or with a phenyl substituent; within each class there are members that have different patterns of hydroxyl group substitution and C-1 oxo or alkyl substitution. Orientational preferences were inferred from the relative binding affinities and were supplemented by computer graphic molecular overlap studies that utilized crystal structures of selected representative compounds and the known tolerance of the estrogen receptor to substituents on the steroidal ligand estradiol. 2-Arylindenes with a 3-aryl substituent appear to orient with the indene system mimicking the A- and B-rings of estradiol (indene/AB mode). This orientation is supported by the fact that hydroxyl substitution at C-6 in the indene markedly elevates binding relative to hydroxyl substitution at the para position of the 2-phenyl substituent. A C-1 oxo substituent increases binding further, but a C-1 alkyl group has little effect. By contrast, the 2-arylindenes with a C-3 ethyl substituent appear to bind with the pendant C-2 ring, mimicking the A-ring of estradiol (pendant/A mode), as hydroxyl substitution in this ring elevates binding relative to the C-6 hydroxy analogues. C-1 alkyl substitution elevates binding affinity in this series; such a substituent in a C-1 S configuration would be projected into the receptor region normally occupied by the high-affinity 7 alpha- or 11 beta-alkyl estradiols. A C-1 oxo substituent produces only a modest binding enhancement in the C-3 ethyl series. A thermodynamic evaluation of receptor fit suggests that the smaller 3-ethyl-2-arylindenes are more efficient than the 2,3-diarylindenes in the use of the molecular bulk to achieve receptor binding. This analysis of the orientational preference of 2-arylindene nonsteroidal estrogens has important implications in the design of donor/acceptor-substituted 2-arylindenes as fluorescent ligands for the estrogen receptor.

Animals↗
PubMed1985

A computational procedure for determining energetically favorable binding sites on biologically important macromolecules.

The interaction of a probe group with a protein of known structure is computed at sample positions throughout and around the macromolecule, giving an array of energy values. The probes include water, the methyl group, amine nitrogen, carboxy oxygen, and hydroxyl. Contour surfaces at appropriate energy levels are calculated for each probe and displayed by computer graphics together with the protein structure. Contours at negative energy levels delineate contours also enable other regions of attraction between probe and protein and are found at known ligand binding clefts in particular. The contours also enable other regions of attraction to be identified and facilitate the interpretation of protein-ligand energetics. They may, therefore, be of value for drug design.

Binding Sites↗
PubMed1985

Synthesis and activity of 5-(aminomethylene)-1,3-cyclohexanediones: enolic analogues of gamma-aminobutyric acid.

Eight 1,3-cyclohexanediones with an aminoalkyl side chain in the 5-position were synthesized as rigid enolic analogues of GABA (gamma-aminobutyric acid). Biochemical investigations about their abilities to displace [3H]GABA and [3H]baclofen [beta-(p-chlorophenyl)-gamma-aminobutyric acid] in binding studies or to inhibit the high-affinity sodium-dependent GABA uptake showed that these compounds were generally devoid of affinity for the two GABA receptors and for the GABA carrier. Only compound 1 exhibited a weak affinity in the GABA-A binding experiments (IC50 = 6.5 X 10(-5) M). Graphic computer modeling was applied in an attempt to explain this activity in comparison to some reference GABA agonists. Electrophysiological studies on dorsal root ganglia (DRG) also excluded agonistic or antagonistic properties on GABA-A or GABA-B receptor models but pointed out an atypical prolongation of Ca2+-dependent action potential for compound 1.

Action Potentials↗
PubMed1986

Structurally specific binding of halogenated biphenyls to thyroxine transport protein.

Prealbumin is a major thyroxine binding protein in blood that has been well studied crystallographically and has also been proposed as a model for the thyroxine nuclear receptor in tissue. The high-affinity T4 binding site in prealbumin gave a linear plot on Scatchard analysis. The interactions of selected polychlorinated biphenyls (PCBs) with prealbumin have been studied with use of computer graphics and predictions made regarding relative binding affinities for such structures. These modeling predictions were tested by using competitive binding experiments involving selected PCBs and hydroxylated derivatives as soluble structural probes. The results are in excellent agreement with the modeling predictions and demonstrated that these compounds can be highly effective (3-8 times better than thyroxine itself) competitive binding ligands for thyroxine specific binding sites in prealbumin. Laterally (3,3',5,5'-) substituted PCBs show the highest binding activity and further substitution on nonlateral (2,2',6,6'-) positions lowers binding activity. Lateral chlorine substitution was common to all PCBs studied that showed high binding affinities. The binding model may also suggest a preference for a linear and symmetrical molecular shape. These structural requirements for binding are substantially consistent with the structure-toxicity relationship for closely related compounds of environmental interest. These specific binding interactions are likely to modulate the distribution of certain PCBs and related compounds and alter hormone-protein interactions that are responsible for the maintenance of normal thyroid status. Since prealbumin is also a model for the putative thyroxine nuclear receptor in tissue, our hypothesis that high toxicity of certain halogenated aromatic hydrocarbons is at least in part due to their thyromimetic properties is further supported.

Binding Sites↗
PubMed1990

An initial three-component pharmacophore for specific serotonin-3 receptor ligands.

With computer modeling, an initial three-component pharmacophore for specific 5-HT3 receptor ligands ICS-205-930 (1), ondansetron (2), zacopride (3), and 3-[2-(guanidinylmethyl)-4-thiazolyl]indol (4) has been identified. Two parts represent electrostatic interactions, one as a hydrogen-bond-donating interaction and the other as a hydrogen-bond-accepting interaction. The third part is represented by a plane in which the lipophilic aromatic groups align. The generation of the pharmacophore relies on the interactions of these ligands with probe atoms representative of a possible hydrogen-bond donor or hydrogen-bond acceptor within the receptor. A carboxylate oxygen was used as a hydrogen-bond-accepting probe and a serine-like hydroxyl was utilized as a hydrogen-bond-donating probe.

Animals↗
PubMed1984

A 1H NMR study of the interactions and conformations of rationally designed brodimoprim analogues in complexes with Lactobacillus casei dihydrofolate reductase.

A consideration of the detailed structural information available from X-ray crystallographic and NMR studies on complexes of dihydrofolate reductase with inhibitors has led to the design of trimethoprim analogues with improved binding properties. Computer graphic techniques have been used to predict which substituent groups were required at the 3'-O position of brodimoprim (2,4-diamino-5-(3,5-dimethoxy-4-bromobenzyl)pyrimidine) to make additional interactions with the enzyme. NMR spectroscopy provided a convenient method of assessing if the analogues were binding in the predicted manner. On the basis of this approach, the C4,C6-dicarboxylic acid analogue IX was designed to interact with Arg-57 and His-28 in the enzyme, and this analogue was found to bind 3 orders of magnitude more tightly than the parent brodimoprim.

Binding Sites↗
PubMed1985

Conformational factors in cardiac glycoside activity.

Gomphoside, a 5 alpha-H cardiac glycoside isolated from Asclepias fructicosa, has an unique double glycosidic linkage to the aglycon through oxygen atoms at 2 alpha and 3 beta of the steroid. The 3'-axial hydroxyl of its conformationally rigid sugar residue appears to be the functional group responsible for its potent inotropic activity. With use of gomphoside as the model compound, the conformation of the flexible glycosidic linkage of the 5 beta-H cardenolides, digitoxigenin alpha-L-rhamnoside and digitoxigenin beta-D-digitoxoside, and the 5 alpha-H cardenolides, uzarigenin alpha-L-rhamnoside and uzarigenin beta-D-6-deoxyalloside, were investigated with the aid of computer graphics and conformational potential energy calculations. The relative inotropic potencies of these cardenolides can be accounted for by considering their active binding conformations with their potential energy distributions. The conformational distribution of the glycosidic moiety was postulated to be the major determinant of the biological activity of these cardenolides.

Animals↗
PubMed1996

Molecular modeling and site-directed mutagenesis studies of a phorbol ester-binding site in protein kinase C.

The protein kinase C (PKC) binding site used by PKC activators such as phorbol esters and diacylglycerols (DAGs) has been characterized by means of molecular modeling and site-directed mutagenesis studies. Based upon a NMR-determined solution structure of the second cysteinerich domain of PKC alpha, molecular modeling was used to study the structures of the complexes formed between the PKC receptor and a number of PKC ligands, phorbol esters, and DAGs. Site-directed mutagenesis studies identified a number of residues important to the binding of phorbol esters to PKC. Analysis of the molecular modeling and mutagenesis results allows the development of a binding model for PKC ligands for which the precise binding nature is defined. The calculated hydrogen bond energies between the protein and various ligands in this binding model are consistent with their measured binding affinities. The binding site for phorbol esters and DAGs is located in a highly conserved, hydrophobic loop region formed by residues 6-12 and 20-27. For the binding elements in phorbol esters, the oxygen at C20 contributes most to the overall binding energy, and that at C3 plays a significant role. The oxygen atom at C12 is not directly involved in the interaction between phorbol esters and PKC. Our results also suggest that the oxygens at C9 and C13 are involved in PKC binding, while the oxygen at C4 is of minimal significance. These results are consistent with known structure-activity relationships in the phorbol ester family of compounds. Comparisons with the X-ray structure showed that although the X-ray data support the results for oxygens at C3, C12, and C20 of phorbol esters, they suggest different roles for oxygens at C4, C9, and C13. Several factors which may contribute to these discrepancies are discussed.

Amino Acid Sequence↗
PubMed1997

Molecular modeling and 3D-QSAR studies on the interaction mechanism of tripeptidyl thrombin inhibitors with human alpha-thrombin.

The mechanism of inhibition of peptidyl inhibitors with thrombin was studied using molecular modeling, molecular mechanics, and CoMFA statistical analysis. A new procedure for the elucidation of binding conformations, BCSPL, is described and was employed to obtain the binding conformers of a series of 18 tripeptidyl thrombin inhibitors. Energetic studies and QSAR analysis of the BCSPL-derived conformers indicated a modest correlation between the calculated binding energies of the title compounds and their inhibitory activities to human alpha-thrombin. CoMFA analysis of the BCSPL alignment resulted in a satisfactory model of the thrombin active site.

Antithrombins↗
PubMed2000

Design and synthesis of Cyclopenta[g]quinazoline-based antifolates as inhibitors of thymidylate synthase and potential antitumor agents(,).

Following the development of raltitrexed, the synthesis of nonpolyglutamatable inhibitors of TS that do not use the reduced folate carrier (RFC) for cellular entry should provide compounds which overcome mechanisms of resistance to folate-based inhibitors of TS that are associated with decreased/altered folylpolyglutamate synthetase (FPGS) expression and/or an impaired RFC. Examination of a computer graphics model of the humanized Escherichia coli TS enzyme with quinazoline inhibitors of TS, such as 1 bound in the active site of the enzyme, suggested that conformational restriction introduced by bridging the C9 with C7 to form a pentacycle may be beneficial for binding to TS. That led to the synthesis of a series of potent cyclopenta[g]quinazoline-based inhibitors of the enzyme in which the glutamyl residue associated with classical antifolates was replaced with a variety of glutamate-derived ligands; the most potent inhibitor being the L-Glu-gamma-D-GluT(alpha) derivative 7j. In the mouse L1210:1565 cell line (mutant RFC), the majority of these compounds had activity equal or only slightly greater compared with the parental L1210 cell line, indicating a reduced dependence on the RFC for cellular uptake in the L1210 cell line.

Animals↗
PubMed2006

Model-free deconvolution of femtosecond kinetic data.

Though shorter laser pulses can also be produced, pulses of the 100 fs range are typically used in femtosecond kinetic measurements, which are comparable to characteristic times of the studied processes, making detection of the kinetic response functions inevitably distorted by convolution with the pulses applied. A description of this convolution in terms of experiments and measurable signals is given, followed by a detailed discussion of a large number of available methods to solve the convolution equation to get the undistorted kinetic signal, without any presupposed kinetic or photophysical model of the underlying processes. A thorough numerical test of several deconvolution methods is described, and two iterative time-domain methods (Bayesian and Jansson deconvolution) along with two inverse filtering frequency-domain methods (adaptive Wiener filtering and regularization) are suggested to use for the deconvolution of experimental femtosecond kinetic data sets. Adaptation of these methods to typical kinetic curve shapes is described in detail. We find that the model-free deconvolution gives satisfactory results compared to the classical "reconvolution" method where the knowledge of the kinetic and photophysical mechanism is necessary to perform the deconvolution. In addition, a model-free deconvolution followed by a statistical inference of the parameters of a model function gives less biased results for the relevant parameters of the model than simple reconvolution. We have also analyzed real-life experimental data and found that the model-free deconvolution methods can be successfully used to get undistorted kinetic curves in that case as well. A graphical computer program to perform deconvolution via inverse filtering and additional noise filters is also provided as Supporting Information. Though deconvolution methods described here were optimized for femtosecond kinetic measurements, they can be used for any kind of convolved data where measured experimental shapes are similar.

Journal Article↗
PubMed1998

A quantitative evaluation of the three dimensional reconstruction of patients' coronary arteries.

BACKGROUND: Through extensive training and experience angiographers learn to mentally reconstruct the three dimensional (3D) relationships of the coronary arterial branches. Graphic computer technology can assist angiographers to more quickly visualize the coronary 3D structure from limited initial views and then help to determine additional helpful views by predicting subsequent angiograms before they are obtained. METHODS: A new computer method for facilitating 3D reconstruction and visualization of human coronary arteries was evaluated by reconstructing biplane left coronary angiograms from 30 patients. The accuracy of the reconstruction was assessed in two ways: 1) by comparing the vessel's centerlines of the actual angiograms with the centerlines of a 2D projection of the 3D model projected into the exact angle of the actual angiogram; and 2) by comparing two 3D models generated by different simultaneous pairs on angiograms. The inter- and intraobserver variability of reconstruction were evaluated by mathematically comparing the 3D model centerlines of repeated reconstructions. RESULTS: The average absolute corrected displacement of 14,662 vessel centerline points in 2D from 30 patients was 1.64 +/- 2.26 mm. The average corrected absolute displacement of 3D models generated from different biplane pairs was 7.08 +/- 3.21 mm. The intraobserver variability of absolute 3D corrected displacement was 5.22 +/- 3.39 mm. The interobserver variability was 6.6 +/- 3.1 mm. CONCLUSIONS: The centerline analyses show that the reconstruction algorithm is mathematically accurate and reproducible. The figures presented in this report put these measurement errors into clinical perspective showing that they yield an accurate representation of the clinically relevant information seen on the actual angiograms. These data show that this technique can be clinically useful by accurately displaying in three dimensions the complex relationships of the branches of the coronary arterial tree.

Adult↗
PubMed1999

Specificity studies of an antibody developed against a mucin-type glycoprotein.

The specificity of a new anti-epiglycanin antibody (AE-3) which recognizes a mucin-type glycoprotein, the Human Carcinoma Antigen, found in the blood of patients with carcinomas, was studied. Information regarding the chemical nature of the antibody binding site was obtained by altering the structure of epiglycanin by chemical or enzymic means and testing the product in a competitive binding assay for inhibition of the binding of AE-3 to epiglycanin. The need for a high molecular weight antigen containing clustered T disaccharide, Gal,1-3GalNAc, was demonstrated. The specificity was further explored by inhibition studies with glycopeptides having one to three mono- to disaccharides. The results were interpreted using computer graphics molecular modeling which predicted the specific recognition of hydroxyl groups on oligosaccharides on adjacent amino acids. Thus T antigen O-linked glycopeptide tumour markers can be designed to be distinguished by antibodies by the amount of clustering of their oligosaccharides.

Amino Acid Sequence↗
PubMed1999

Internal motion time scales of a small, highly stable and disulfide-rich protein: a 15N, 13C NMR and molecular dynamics study.

Motions of the backbone C alpha H alpha and threonine C beta H beta bonds of toxin alpha were investigated using natural abundance 13C NMR and molecular dynamics. Measurement of the 13C longitudinal and transverse relaxation rates employed ACCORDION techniques together with coherence selection by pulsed field gradients and sensitivity enhancement through the use of preservation of equivalent pathway, thus allowing a considerable reduction of the required spectrometer time. 13C R1, R2, 1H-->13C NOE were obtained, as well as the variations of R1 rho (90 degrees) as a function of the rf field strength. These data were compared to those recorded by 1H and 15N NMR on a labelled sample of the toxin [Guenneugues et al. (1997) Biochemistry, 36, 16097-16108]. Both sets of data showed that picosecond to nanosecond time scale motions are well correlated to the secondary structure of the protein. This was further reinforced by the analysis of a 1 ns molecular dynamics simulation in water. Several C alpha H alpha and threonine C beta H beta experimentally exhibit fast motions with a correlation time longer than 500 ps, that cannot be sampled along the simulation. In addition, the backbone exhibits motions on the microsecond to millisecond time scale on more than half of its length. Thus, toxin alpha, a highly stable protein (Tm = 75 degrees C at acidic pH) containing 61 amino acids and 4 disulfides, shows important internal motions on time scales ranging from 0.1-0.5 ps, to 10-100 ps, 1 ns, and about 30 microseconds to 10 ms.

Aprotinin↗