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At least 415 records · Page 23Linked to original sources
PubMed1998

[Three-dimensional facial reconstruction of computerized tomography images by computer-aided design: example of an anthropologic study].

Thanks to the medical scanning techniques and the reliability of some applications programs in 3D reconstruction, we are now able to explain an observation methodology based on the example of an anthropology study on Egyptian mummies'heads through a non-destructive proceeding. We have managed to demonstrate the exploration of the cervicofacial anatomy in the three dimensions of space and the possibility of dissociating the different anatomical tissues. The authors would like to point out the various consequences such a methodology may engender in any field.

Adult↗
PubMed1987

Computer-aided design and physiological testing of a luteinising hormone-releasing hormone analogue for 'adjuvant-free' immunocastration.

An analogue of LHRH containing an extension of Gly-Cys at the carboxyl-terminus has been designed to permit reproducible coupling to a suitably modified carrier via a thioether bond. Potential energy calculations indicated that this analogue adopted a conformation in solution virtually identical to the type II' turn around Gly-6-Leu-7 predicted for native LHRH. Intradermal administration of a conjugate of this analogue with purified protein derivative of tuberculin to male rats previously primed with BCG vaccine rapidly led to complete testicular regression. This adjuvant-free immunisation protocol may represent an alternative to castration for the veterinary control of reproductive function.

Animals↗
PubMed2000

Safety and computer-aided design of chemotherapy plans.

Previously, generic principles were derived empirically from examples of reasoning about the efficacy and safety of chemotherapy. Some of the principles were used in a prototype decision-support system for managing patients through chemotherapy. It reminded clinicians which, how, and when drugs were to be given; suggested treatment modifications as a result of detected adverse events; and warned how unplanned actions undermine efficacy or exacerbate hazardous side effects. Here, we investigate the reuse of these safety principles to generate symbolic and textual representations of new chemotherapy plans. In clinical trials of chemotherapy, a written protocol is essential, especially in obtaining ethical approval. The symbolic representation, from which textual extracts are derived, can be used in conjunction with software for managing chemotherapy.

Antineoplastic Agents↗
PubMed1986

Computer-aided design of artificial enzymes: cyclic urea mimetics of alpha-chymotrypsin.

We use molecular mechanics to calculate the conformational properties of a cyclic urea mimetic of alpha-chymotrypsin proposed, but not yet synthesized, by Cram and co-workers. We find that, in order to bring the structural elements of the catalytic triad into a spatial orientation suitable for proton transfer, the proposed enzyme mimetic must adopt a highly strained conformation. We redesign that part of the molecular architecture holding the catalytic triad in position and suggest two alternative enzyme mimetics. Of these, we find that the mimetic containing a fused ring structure positions the components of the catalytic triad at reasonable distances for proton transfer. We study the effect of these structural alterations on the recognition pattern presented by the enzyme mimetic to the substrate, as illustrated by the molecular electrostatic potential of the artificial enzyme.

Chymotrypsin↗
PubMed1979

NCTR computer systems designed for toxicologic experimentation. V. Post-experiment information system.

The Post-Experiment Information System (PEIS) is an automated data collection and reporting system composed of three specialized subsystems: Pathology, Chemistry and Microbiology. These subsystems function either independently or collectively to construct and maintain a comprehensive data base of all experimental values derived from, or associated with, an animal carcass. All data are retrievable by the unique Carcass Identification (CID) number assigned at death, which is the correlative of the Unique Identification Number (UIN) assigned to the animal at birth and used throughout its lifespan. Elements processed under the PEIS include gross and microscopic pathological observations, organ weights, hematologic data, chemical data, and microbiological analyses. The ability of the system to integrate the post-experiment data with the information collected on an animal from birth (BIS) and during the experiment (EIS) provides a complete animal history to the Principal Investigator or other requestor.

Animals↗
PubMedDate not supplied

NCTR computer systems designed for toxicologic experimentation. IV. Experiment information system.

The Experiment Information System (EIS) is a computerized data collection, maintenance, and reporting system for specified information values collected during the lifespan of animals assigned to toxicologic investigations at NCTR. The system records and/or controls experimental variables, which might ultimately affect the results, through the operation and integration of the Diet Preparation Subsystem (DPS), the Environmental Monitoring Subsystem (EMS), the Microbiology Subsystem (MBS), and the Chemistry Data Subsystem (CDS). The fifth component of the EIS, the Experimental Data Collection Subsystem (EDCS), is responsible for handling all data generated by, or attributed to, the animals from assignment until death or removal. Through integration of these five subsystems, the history of an animal while on study is recorded and stored for later recall. In addition, "routine" and "special" reports are made available through the system software which enables stringent control of the experiment by the Principal Investigator, Animal Husbandry, and NCTR Management.

Animals↗
PubMedDate not supplied

Continuous registration of cardiac output with a new computer system designed for hot-film anemometry: an in vitro study.

We have developed and improved a method for the continuous on-line registration of cardiac output. By measuring blood velocity with a hot-film anemometer probe in the pulmonary artery, cardiac output can be estimated by gated systolic integration of the velocity signals. The integrated value for a certain period can be converted to a cardiac output proportional value. A thermistor placed next to the velocity probe enables thermodilution measurement of cardiac output, which serves as in vivo and in situ calibration. In this paper an in vitro study of the method applied to pulsatile flow is presented. A good correlation was found between real flow and both the velocity method and the thermodilution method. Fluid temperature and changing stroke volume and/or pulse frequency had minimal influence on accuracy, whereas altered probe position required recalibration for the velocity method but not for the thermodilution method. The advantages of the velocity method for the measurement of cardiac output are: The continuous on-line monitoring of cardiac output. The need for the injection of only very small volumes of cold saline, as the frequency of thermodilution measurements is reduced.

Cardiac Output↗
PubMedDate not supplied

[Computer module design of the parametric structure of water].

The algorithms of module design and the results of constructing the parametric structures of water were considered. The tetrahedral electron structure of the oxygen atom of water, which is a double symmetric donor and acceptor of protons, was taken as the main postulate. As opposed to the crystal lattices of diamond and ice, the hexacycle twist-bath was considered as the basic element of the original structure. A great variety of possible structures were obtained, which involve quasi-unidimensional (helices, rods), dendrite-like, ring-shaped, planar, and fractal structures, as well as combinatoric structures composed of these forms. The functions of distribution of valence angles in fractal structures optimized with respect to energy have two main maxima at 104 and 112 degrees, as differentiated from the starting ideal tetrahedral angle of 109.5 degrees. Changes in, and the accumulation of elastic energy of distortions of rod structure of different symmetry were analyzed. This energy can be utilized during the conformational changes of biopolymers. The substantial difference in the solubility of two anomeric forms of glucose is explained by a different degree of conformity of the glucose molecule structure to the structure of bound water.

Computer Simulation↗
PubMed2003

Computer-aided design of a factor Xa inhibitor by using MCSS functionality maps and a CAVEAT linker search.

We have investigated a new approach to efficiently find a novel inhibitor against a serine protease (i.e. an activated coagulation factor X, FXa) by using de novo design programs and the X-ray crystal structure of the target enzyme. FXa is a coagulant enzyme that generates thrombin (a serine protease) and participates in both intrinsic and extrinsic coagulation pathways. We adopted multiple copy simultaneous search (MCSS) and CAVEAT linker search techniques, which disclosed a novel FXa inhibitor (T01312) consisting of two binding moieties (the benzamidinyl and adamantyl groups) and a linker unit (the carboxybenzylamine group). The inhibitory activity of T01312 against FXa was determined to be a small K(i)-value of 48nM, which is two orders of magnitude smaller than that against thrombin. An X-ray crystal analysis of T01312 complexed with trypsin (an analogue of FXa) and docking studies of T01312 with trypsin and FXa showed that: (i) the benzamidinyl group is a predominant binding moiety in the anionic pocket (S1 site) with an asparatic acid residue; (ii) a hydrophobic pocket (S4 site) is the binding site of the adamantyl group; (iii) the carboxylate group of the linker contributes to the selectivity for FXa against thrombin. Thus, the combination of the knowledge of the X-ray crystal structure of the target molecule with MCSS and CAVEAT linker search techniques proved to be an effective hit-finding method that does not require the screening of huge compound libraries.

Antithrombin III↗
PubMed2005

Atom, atom-type, and total nonstochastic and stochastic quadratic fingerprints: a promising approach for modeling of antibacterial activity.

The TOpological MOlecular COMputer Design (TOMOCOMD-CARDD) approach has been introduced for the classification and design of antimicrobial agents using computer-aided molecular design. For this propose, atom, atom-type, and total quadratic indices have been generalized to codify chemical structure information. In this sense, stochastic quadratic indices have been introduced for the description of the molecular structure. These stochastic fingerprints are based on a simple model for the intramolecular movement of all valence-bond electrons. In this work, a complete data set containing 1006 antimicrobial agents is collected and presented. Two structure-based antibacterial activity classification models have been generated. The models (including nonstochastic and stochastic indices) classify correctly more than 90% of 1525 compounds in training sets. These models permit the correct classification of 92.28% and 89.31% of 505 compounds in an external test sets. The TOMOCOMD-CARDD approach, also, satisfactorily compares with respect to nine of the most useful models for antimicrobial selection reported to date. Finally, a virtual screening of 87 new compounds reported in the antiinfective field with antibacterial activities is developed showing the ability of the TOMOCOMD-CARDD models to identify new leads as antibacterial.

Anti-Bacterial Agents↗
PubMed2001

Computer-aided design of beta-sheet peptides.

The design of beta-sheet proteins is still a challenge in the field of de novo protein design. Here, we have tested the validity of automatic design methods to create and/or improve beta-sheet peptides and proteins. We chose Betanova, a three-stranded beta-sheet peptide, as target system, and, as an automatic design tool, a protein design algorithm called PERLA (protein engineering rotamer library algorithm). PERLA was used to define both stabilising and destabilising single- and multiple-residue mutations of Betanova. Conformational analysis by NMR spectroscopy and far-UV circular dichroism (CD) allowed us to evaluate population differences among the set of designed peptides. Some of the new mutants are approximately 1 kcal/mol more stable than the wild-type peptide. Comparison of the scale of predicted and observed stabilities demonstrates that they are in good agreement for most peptides studied. Our results show that automatic design algorithms can be successfully applied to the design of beta-sheet peptides.

Algorithms↗
PubMed1993

A burn patient resuscitation therapy designed by computer simulation (BET). Part 2: Initial clinical validation.

The clinical results obtained from the first 40 burned patients resuscitated with 220 ml/h x BBSA (m2) of human serum albumin with concentrations of 10, 7.5, 5 and 2.5 per cent in lactated Ringer's (0-8, 8-16, 16-24 and 24-40 h post injury respectively), which we have called BET fluid therapy, were compared with those obtained in 58 patients resuscitated with lactated Ringer's 4 ml/kg of body weight/%BBSA during the first 24 h after burning. The results confirm the effectiveness of the BET form of fluid therapy during the shock phase after burning. The BET fluid therapy method differs from other procedures because of its lower volume of infused resuscitation solution with the rapid infusion of large amounts of colloid. These preliminary results have encouraged us to continue analysing this new method of fluid therapy.

Adolescent↗
PubMed1999

Computer-Aided Design (CAD) of Synzymes: Use of Molecular Mechanics (MM) for the Rational Design of Superoxide Dismutase Mimics.

Mn(II) complexes of C-substituted macrocyclic 1,4,7,10,13-pentaazacyclopentadecane ligands have been shown to be excellent functional mimics (Synzymes) of the native enzyme manganese superoxide dismutase (Mn SOD). To better understand the profound effects that substituents exert on the SOD catalytic activity, we have utilized molecular mechanics (MM) calculations employing the CAChe system. Such a conformational analysis has made it possible to develop a consistent model that correlates catalytic rate with the ability of the ligand to adopt a folded geometry about the high-spin d(5) spherically symmetrical Mn(II) ion, thus affording a six-coordinate pseudo-octahedral geometry (the geometry required by Mn(III)). This conformational analysis is consistent with the model that one of the nitrogen donors of the pentaaza crown ligand folds to occupy a pseudo-axial coordination position of an octahedron. The DeltaE between the lowest energy folded ligand structure about Mn(II) and its corresponding Mn(III) structure correlates with catalytic activity; i.e., for a large series of complexes an excellent correlation is obtained for both the inner-sphere and outer-sphere rate constants for oxidation of Mn(II)-the rate-determining step in the catalytic cycle for these SOD mimics. From single-crystal X-ray structure determinations on several different members of this class of 7-coordinate dichloro(pentaaza crown) Mn(II) complexes, we have observed that the arrangement of NH's of the secondary amine donors is such that they alternate in their relative orientation to the plane generated by the five nitrogens and the Mn; i.e., the NH's are arranged in an up-down-up-down-up stereochemistry. Thus, one side of the plane of the macrocyclic ring possesses two nonadjacent NH's, while the opposite side has three NH's. Two unique folding motifs generated from MM calculations are found to correlate with the two pathways for Mn(II) oxidation: (1) the inner-sphere path correlates with an NH from the side of the two NH's folding into the axial octahedral coordination site, and (2) the outer-sphere path correlates with an NH from the side of the three NH's folded into an axial O(h) site. MM calculations allow one to probe the effect that substituents on the macrocyclic ring carbons have on the relative energies of the Mn(II) and Mn(III) complexes with these ligands in the various potential folded geometries. The details of this modeling paradigm and the results of MM calculations utilizing the folding motif for a large number complexes are described. Of particular significance is the ability of the MM tool to predict correctly that certain substituent patterns and substituents enhance or reduce the contribution of one or the other pathway to the overall catalytic rate. The syntheses of several new complexes are reported and the rate constants for the two pathways of Mn(II) oxidation have been measured and found to correlate with the predictions arising from the energetics of folding as calculated by MM calculations.

Journal Article↗
PubMed2002

Computer-aided design of selective COX-2 inhibitors: comparative molecular field analysis, comparative molecular similarity indices analysis, and docking studies of some 1,2-diarylimidazole derivatives.

Comparative molecular field analysis and comparative molecular similarity indices analysis were performed on 114 analogues of 1,2-diarylimidazole to optimize their cyclooxygenase-2 (COX-2) selective antiinflammatory activities. These studies produced models with high correlation coefficients and good predictive abilities. Docking studies were also carried out wherein these analogues were docked into the active sites of both COX-1 and COX-2 to analyze the receptor ligand interactions that confer selectivity for COX-2. The most active molecule in the series (53) adopts an orientation similar to that of SC-558 (4-[5-(4-bromophenyl)-3-trifluoromethyl-1H-1-pyrozolyl]-1-benzenesulfonamide) inside the COX-2 active site while the least active molecule (101) optimizes in a different orientation. In the active site, there are some strong hydrogen-bonding interactions observed between residues His90, Arg513, and Phe518 and the ligands. Additionally, a correlation of the quantitative structure-activity relationship data and the docking results is found to validate each other and suggests the importance of the binding step in overall drug action.

Binding Sites↗