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At least 667 records · Page 37Linked to original sources
PubMed2001

3-D-QSAR/CoMFA and recognition models of benzimidazole derivatives at the 5-HT(4) receptor.

3-D-QSAR/CoMFA methodology and computational simulation of ligand recognition have been successfully applied to explain the binding affinities of a series of benzimidazole derivatives 1-24 acting at serotonin 5-HT(4)Rs. Both derived computational models have facilitated the identification of the structural elements of the ligands that are key to high 5-HT(4)R affinity. The results provide the tools for predicting the affinity of related compounds, and for guiding the design and synthesis of new ligands with predetermined affinities and selectivity.

Benzimidazoles↗
PubMed1996

Does DNA compute? Molecular computing.

The demonstration that DNA molecules can act as parallel processors to solve hard problems has excited interest in the possibility of developing molecular computers based on recombinant DNA techniques.

Base Sequence↗
PubMed2003

Automated preparation of 188Re-labeled radiopharmaceuticals for endovascular radiation therapy.

We have developed an automated system for the preparation of highly concentrated 188Re-perrhenate, diethylenetriamine pentaacetic acid (DTPA) and mercaptoacetyltriglycine (MAG3). The three procedural steps include concentration of 188Re-perrhanerate, chelation and purification and sterilization. The steps are operated by a small micro-controller. The eluted 188Re-perrhenate of 15 GBq/18 ml from 37 GBq 188W/188Re-generator was concentrated to 1.2 ml in 10 +/- 0.5 min with a recovery yield of 95 +/- 1.5%. We obtained the highest radiochemical yield of 95.4 +/- 2.8% and 98.5 +/- 1.2% for 188Re-DTPA and MAG3 at the oil bath temperatures of 95-97 degrees C and 93-97 degrees C, respectively.

Brachytherapy↗
PubMed1995

Implementing a computer-assisted appropriateness review using DRG 182/183.

BACKGROUND: The focus on patient outcomes as performance measures and on processes of care as systems to improve is intensifying. Nevertheless, appropriateness reviews are likely to remain essential (for example, studies evaluating inpatient admission, laboratory testing, invasive procedures, and discharge planning) for several reasons. METHODS: Forbes Regional Hospital (Monroeville, PA) undertook to redesign the process of appropriateness reviews using a computer-assisted methodology. The change was predicated on accessing electronically recorded clinical data collected as part of a state-mandated discharge reporting requirement. RESULTS: More than 90% of diagnosis-related group 182/183 (gastrointestinal/esophagitis) admissions were deemed appropriate on the basis of later manual reviews. This redesign was accomplished at no added expense while the amount of time required to complete the study was decreased. The ability to easily examine relationships identified during the evaluation was also expanded. The experience led to greater enthusiasm on the part of the medical staff to pursue more quality improvement projects. Creation of software programs that can be used repeatedly, modified to change existing thresholds, or expanded to include other conditions was another benefit. Clinicians gained valuable experience and familiarity with information systems. Lastly, all this was accomplished without purchasing new hardware, acquiring updated software, or relying on the presence of an electronic medical record.

Concurrent Review↗
PubMed2000

GB/SA water model for the Merck molecular force field (MMFF).

A revised generalized Born/surface area (GB/SA) continuum solvation model has been developed for water that is compatible with the Merck molecular force field (MMFF). This model gives free energies of aqueous solvation that are comparable in accuracy to the original water model when the OPLS* force field is employed. The average unsigned error in aqueous deltaGsol using the new water model and MMFF is 0.62 kcal/mol for a training set of 82 solutes compared to 1.24 kcal/mol for the original GB/SA water model and MMFF. The average unsigned errors for 47 neutral solutes outside the training set and 10 ions are 0.96 and 2.32 kcal/mol, respectively. By comparison, the average errors for the test set and ions using the original GB/SA water model are 1.76 and 5.32 kcal/mol. This revised parameter set provides a more accurate representation of aqueous solvation for use with MMFF.

Artificial Intelligence↗
PubMed2002

Dbtop: topomer similarity searching of conventional structure databases.

A new topomer-based method for 3D searching of conventional structural databases is described, according to which 3D molecular structures are compared as sets of fragments or topomers, in single rule-generated conformations oriented by superposition of their fragmentation bonds. A topomer is characterized by its CoMFA-like steric shape and now also by its pharmacophoric features, in some novel ways that are detailed and discussed. To illustrate the behavior of topomer similarity searching, a new dbtop program was used to generate a topomer distance matrix for a diverse set of 26 PDE4 inhibitors and 15 serotonin receptor modulators. With the best of three parameter settings tried, within the 210 shortest topomer distances (of 1460), 94.7% involved pairs of compounds having the same biological activity, and the nearest neighbor to every compound also shared its activity. The standard similarity metric, Tanimoto coefficients of "2D fingerprints", could achieve a similar selectivity performance only for the 108 shortest distances, and three Tanimoto nearest neighbors had a different biological activity. Topomer similarity also allowed "lead-hopping" among 22 of the 26 PDE4 inhibitors, notably between rolipram and cipamfylline, while 2D fingerprints" Tanimotos recognized similarity only within generally recognized structural classes. In 370 searches of authentic high-throughput screening (HTS) data sets, the typical topomer similarity search rate was about 200 structures per s.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1997

Neutral networks in protein space: a computational study based on knowledge-based potentials of mean force.

BACKGROUND: Many protein sequences, often unrelated, adopt similar folds. Sequences folding into the same shape thus form subsets of sequence space. The shape and the connectivity of these sets have implications for protein evolution and de novo design. RESULTS: We investigate the topology of these sets for some proteins with known three-dimensional structure using inverse folding techniques. First, we find that sequences adopting a given fold do not cluster in sequence space and that there is no detectable sequence homology among them. Nevertheless, these sequences are connected in the sense that there exists a path such that every sequence can be reached from every other sequence while the fold remains unchanged. We find similar results for restricted amino acid alphabets in some cases (e. g. ADLG). In other cases, it seems impossible to find sequences with native-like behavior (e.g. QLR). These findings seem to be independent of the particular structure considered. CONCLUSIONS: Amino acid sequences folding into a common shape are distributed homogeneously in sequence space. Hence, the connectivity of the set of these sequences implies the existence of very long neutral paths on all examined protein structures. Regarding protein design, these results imply that sequences with more or less arbitrary chemical properties can be attached to a given structural framework. But we also observe that designability varies significantly among native structures. These features of protein sequence space are similar to what has been found for nucleic acids.

Amino Acids↗
PubMed1999

Computational studies of the development of functionally specialized neural modules.

Three hypotheses about the activity-dependent development of functionally specialized neural modules are discussed in this review. These hypotheses state that: (1) a combination of structure function correspondences plus the use of competition between neural modules leads to functional specializations; (2) parcellation is due to a combination of neural selectionism, the idea that learning results from a stabilization of some neural connections and the elimination of others, and a locality constraint, which states that connections between nearby neurons are more easily stabilized than those between distant neurons; and (3) a temporal and spatial modulation of plasticity can induce higher functional development in later-developing parts of the nervous system relative to earlier-developing parts. All three hypotheses have been implemented and evaluated in computational models. Limitations of current neuroscientific methodologies mean that computer simulation provides one of the only tools available for evaluating and refining our large-scale theories of the development of functionally specialized neural modules.

Journal Article↗
PubMed1998

Genomics and computational molecular biology.

There has been a dramatic increase in the number of completely sequenced bacterial genomes during the past two years as a result of the efforts both of public genome agencies and the pharmaceutical industry. The availability of completely sequenced genomes permits more systematic analyses of genes, evolution and genome function than was otherwise possible. Using computational methods - which are used to identify genes and their functions including statistics, sequence similarity, motifs, profiles, protein folds and probabilistic models - it is possible to develop characteristic genome signatures, assign functions to genes, identify pathogenic genes, identify metabolic pathways, develop diagnostic probes and discover potential drug-binding sites. All of these directions are critical to understanding bacterial growth, pathogenicity and host-pathogen interactions.

Bacterial Proteins↗
PubMed2000

Application of the component paradigm for analysis and design of advanced health system architectures.

Based on the component paradigm for software engineering as well as on a consideration of common middleware approaches for health information systems, a generic component model has been developed supporting analysis, design, implementation and harmonisation of such complex systems. Using methods like abstract automatons and the Unified Modelling Language (UML), it could be shown that such components enable the modelling of real-world systems at different levels of abstractions and granularity, so reflecting different views on the same system in a generic and consistent way. Therefore, not only programs and technologies could be modelled, but also business processes, organisational frameworks or security issues as done successfully within the framework of several European projects.

Computer Simulation↗
PubMed2001

A systematic approach for analysis and design of secure health information systems.

A toolset using object-oriented techniques including the nowadays popular unified modelling language (UML) approach has been developed to facilitate the different users' views for security analysis and design of health care information systems. Paradigm and concepts used are based on the component architecture of information systems and on a general layered security model. The toolset was developed in 1996/1997 within the ISHTAR project funded by the European Commission as well as through international standardisation activities. Analysing and systematising real health care scenarios, only six and nine use case types could be found in the health and the security-related view, respectively. By combining these use case types, the analysis and design of any thinkable system architecture can be simplified significantly. Based on generic schemes, the environment needed for both communication and application security can be established by appropriate sets of security services and mechanisms. Because of the importance and the basic character of electronic health care record (EHCR) systems, the understanding of the approach is facilitated by (incomplete) examples for this application.

Computer Security↗
PubMed1996

Comparative modeling of substrate binding in the S1' subsite of serine carboxypeptidases from yeast, wheat, and human.

Human cathepsin A ("lysosomal protective protein"; E.C.3.4.16.5) is a multifunctional lysosomal protein which forms a high-molecular-weight complex with beta-galactosidase and alpha-neuraminidase, protecting them against intralysosomal proteolysis. In addition to this protective function, cathepsin A is a serine carboxypeptidase and the understanding of its catalytic function requires a definition of its substrate specificity. For this purpose, we used a combined experimental [Pshezhetsky, A. V., Vinogradova, M. V., Elsliger, M.-A., El-Zein, F., Svedas, V.K., & Potier, M. (1995) Anal. Biochem. 230, 303-307] and theoretical approach comparing cathepsin A to two different homologous carboxypeptidases of the same family: yeast carboxypeptidase Y and wheat carboxypeptidase II. We computed the energies involved in substrate binding to the S1' subsite (C-terminal) of cathepsin A using a structural model based on the X-ray structure of the homologous wheat carboxypeptidase II. The binding energies of N-blocked Phe-Xaa dipeptide substrates to the active sites of cathepsin A, wheat carboxypeptidase II, and yeast carboxypeptidase Y were estimated using a molecular mechanics force field supplemented with a solvation energy term. This theoretical analysis showed a good correlation with the experimentally determined free energies of substrate binding. This result validates the use of this approach to analyze the energetics of substrate binding to the S1' subsite and provides a rational interpretation of serine carboxypeptidase-substrate interactions in molecular terms. We conclude that the three serine carboxypeptidases have similar affinities for substrates with hydrophobic P1' amino acid residues but that the wheat enzyme has an additional capacity for binding positively charged P1' residues. Finally, the substrate specificity of human cathepsin A is very similar to that of carboxypeptidase Y, with a high binding affinity for substrates with hydrophobic P1' residues, but the affinity of cathepsin A for P1; Phe residue is higher than for the Leu residue.

Binding Sites↗
PubMedDate not supplied

Evaluation of descriptors and mini-fingerprints for the identification of molecules with similar activity.

Combinations of 65 preferred 1D/2D molecular descriptors and 143 single structural keys were evaluated for their performance in compound classification focused on biological activity. The analysis was based on principal component analysis of descriptor combinations and facilitated by use of a genetic algorithm and different scoring functions. In these calculations, several descriptor combinations with greater than 95% prediction accuracy were identified. A set of 40 preferred structural keys was incorporated into a small binary fingerprint designed to search databases for compounds with biological activity similar to query molecules. The performance of mini-fingerprints was tested by systematic similarity search calculations in a database consisting of compounds belonging to seven biological activity classes, which had not been used to select effective descriptors. In these blind test calculations, mini-fingerprints correctly identified approximately 54% of compounds sharing similar biological activity and with 1% false positives. Thus, although the design of mini-fingerprints is conceptually simple, they perform well in activity-oriented similarity searching.

Computing Methodologies↗
PubMedDate not supplied

A Chinese Postman Problem based on DNA computing.

DNA computing is a novel method for solving a class of intractable computational problems, in which the computing can grow exponentially with the problem size. Up to now, many accomplishments have been achieved to improve its performance and increase its reliability. A Chinese Postman Problem has been solved by means of molecular biology techniques in the paper. A small graph was encoded in molecules of DNA, and the "operations" of the computation were performed with standard protocols and enzymes. This work represents further evidence for the ability of DNA computing to solve NP-complete search problems.

Base Sequence↗
PubMedDate not supplied

Design and evaluation of a molecular fingerprint involving the transformation of property descriptor values into a binary classification scheme.

A new fingerprint design concept is introduced that transforms molecular property descriptors into two-state descriptors and thus permits binary encoding. This transformation is based on the calculation of statistical medians of descriptor distributions in large compound collections and alleviates the need for value range encoding of these descriptors. For binary encoded property descriptors, bit positions that are set off capture as much information as bit positions that are set on, different from conventional fingerprint representations. Accordingly, a variant of the Tanimoto coefficient has been defined for comparison of these fingerprints. Following our design idea, a prototypic fingerprint termed MP-MFP was implemented by combining 61 binary encoded property descriptors with 110 structural fragment-type descriptors. The performance of this fingerprint was evaluated in systematic similarity search calculations in a database containing 549 molecules belonging to 38 different activity classes and 5000 background molecules. In these calculations, MP-MFP correctly recognized approximately 34% of all similarity relationships, with only 0.04% false positives, and performed better than previous designs and MACCS keys. The results suggest that combinations of simplified two-state property descriptors have predictive value in the analysis of molecular similarity.

Computing Methodologies↗
PubMedDate not supplied

An approach to comparative analysis of chromatographic fingerprints for assuring the quality of botanical drugs.

The present study was focused on developing the chemometric methods for analysis of the chromatographic fingerprint to control the quality of botanical drugs, which has gained attention in Asia and other countries. We developed a novel approach to generate a set of fingerprint features, called Fisher components (FCs) that were extracted from the chromatographic fingerprint. The method greatly reduces the dimensionality of the fingerprint vector, and the resulting FCs still retain most discriminatory information of the original fingerprint. Choosing an example of relevance to contemporary botanical drugs, we applied the FCs to a set of Shenmai injection samples. We successfully identified the manufacturers of the samples using two classifiers, linear discriminant analysis (LDA) and k-Nearest Neighbor (k-NN) based on the FCs. We also applied a similarity assessment together with the visual analysis using the FCs to exam the products from different manufacturers. We found that the lot-to-lot consistency of products can be accurately determined using the FCs. Finally, we demonstrated that the application of chemometric methods for chromatographic fingerprinting offers reliability to detect suspected fraud samples. In summary, we demonstrated that the presented approaches could be useful to determine the identity, consistency, and authenticity of Shenmai injection through chromatographic fingerprinting. The methods are equally applicable to other botanical drugs.

Chromatography↗