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Biomedical subjects

D Horvath

Publications and source records attributed to D Horvath.

At least 19 recordsLinked to original sources
PubMed2001

From hit to lead. Combining two complementary methods for focused library design. Application to mu opiate ligands.

Compound 1 obtained by random screening and displaying a micromolar activity on the mu opiate receptor was chosen as a starting point for optimization. Two complementary concepts of similarity were used for the design of analogues and compared. These are based, respectively, on a computer-aided comparison of pharmacophoric patterns and on topological similarity. The structure-activity relationships are discussed in light of both similarity concepts. Compound 40, an N-methyl-3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decyl)acetamide derivative, designed by combining the structure-activity relationships enlightened by each method, has a subnanomolar affinity for mu (h) receptor (IC(50) = 0.9 nM). It is a promising lead, allowing the design of a new series of analogues substituted at the N-3 of the spirocycle moiety.

Animals↗
PubMed2001

From hit to lead. Analyzing structure-profile relationships.

Two compounds, obtained by random screening, and displaying micromolar activities on the mu opiate receptor were used as starting points for optimization. In that work, the traditional concept of the activity of a compound (related to one or a few targets) was extended to the comprehensive pharmacological profile of that compound on more than 70 receptors, transporters, and channels relevant to a CNS-oriented project. Using the two complementary design strategies based on two similarity concepts described in the previous paper, we have obtained analogues with IC(50) values ranging between 0.9 nM and a few micromolar on the mu receptor and displaying qualitatively different profiles. We discuss here, both on a case-by-case basis and from a statistical standpoint, the pharmacological profiles in light of the two similarity concepts.

Brain↗
PubMed2001

Recursive Partitioning analysis of mu-opiate receptor high throughput screening results.

Recursive Partitioning (RP) was used to analyze a heterogeneous data set of mu receptor High Throughput Screening results of combinatorial libraries, lead optimization products and reference opiate ligands from literature. Different sets of molecular descriptors and various parameterization schemes have been systematically assessed in search for an optimal RP tree, best discriminating between mu receptor ligands and inactive molecules. This discriminating ability has been evaluated in terms of a quality criterion (representing an enrichment factor corrected by the retrieval rate of active compounds), for both the learning set--with and without performing a cross-validation test--and a distinct validation set. The non-linearity of the approach, as well as the very large number of degrees of freedom of the models, render the statistical analysis--in particular, the detection of overfitting--quite difficult. The advantages and disadvantages of the RP approach are discussed on hand of the comparative analysis of the performances of the models under the studied conditions. Eventually, the features highlighted by the RP model as essential sources for the activity of compounds with respect to the mu receptor are analyzed in the light of commonly accepted mu receptor binding hypotheses. It is shown that the RP model considered to be "optimal" due to its simultaneous success in the cross-validation and validation simulations has been able to "discover" the existence of the two main ("morphine-like" and "meperidine-like") mu ligand families, represented as the two main "active nodes" of this tree.

Drug Evaluation, Preclinical↗
PubMed1998

Glucocorticoid-inducible expression of a bacterial avirulence gene in transgenic Arabidopsis induces hypersensitive cell death.

Pathogenic strains of Pseudomonas syringae pv. tomato carrying the avrRpt2 avirulence gene specifically induce a hypersensitive cell death response in Arabidopsis plants that contain the complementary RPS2 disease resistance gene. Transient expression of avrRpt2 in Arabidopsis plants having the RPS2 gene has been shown to induce hypersensitive cell death. In order to analyze the effects of conditional expression of avrRpt2 in Arabidopsis plants, transgenic lines were constructed that contained the avrRpt2 gene under the control of a tightly regulated, glucocorticoid-inducible promoter. Dexamethasone-induced expression of avrRpt2 in transgenic lines having the RPS2 gene resulted in a specific hypersensitive cell death response that resembled a Pseudomonas syringae-induced hypersensitive response and also induced the expression of a pathogenesis-related gene (PR1). Interestingly, high level expression of avrRpt2 in a mutant rps2-101C background resulted in plant stress and ultimately cell death, suggesting a possible role for avrRpt2 in Pseudomonas syringae virulence. Transgenic RPS2 and rps2 plants that contain the glucocorticoid-inducible avrRpt2 gene will provide a powerful new tool for the genetic, physiological, biochemical, and molecular dissection of an avirulence gene-specified cell death response in both resistant and susceptible plants.

Arabidopsis↗
PubMed1998

Cleveland Clinic continuous flow blood pump: progress in development.

The Cleveland Clinic continuous flow blood pump is the central element of our innovative ventricular assist system (IVAS). Recent progress has been made in the design/fabrication of a pulsatile mock loop, journal bearing materials testing, and evaluation of a system control algorithm. These results have allowed an acceleration of our program.

Algorithms↗
PubMed1997

A virtual screening approach applied to the search for trypanothione reductase inhibitors.

A prediction algorithm of the binding affinity of ligands to trypanothione reductase (TR), the enzyme replacing glutathione reductase in the metabolism of trypanosomatidae, has been used for the "virtual screening" of a data base of 2500 molecular sketches and has detected several structures of putative TR ligands. Most of these compounds turned out to be micromolar inhibitors of TR, as predicted by the algorithm. While their inhibitory potencies are lower than those of previously reported compounds, one of the molecules reported here could represent the lead toward a structurally different class of TR inhibitors. The fully automated prediction algorithm converts the 2D molecular sketches into 3D ligand structures, explores the conformational space of the latter, and performs a grid-based, rigid-body docking of the resulting family of ligand conformations into the TR site, calculating enthalpic and entropic binding indexes and predicting the binding affinity. The docking model has also been used to obtain hints about the binding modes of TR ligands.

Algorithms↗
PubMed1996

2-Amino diphenylsulfides as inhibitors of trypanothione reductase: modification of the side chain.

A molecular modeling study meant to detect pharmacophore-like patterns in the active site of trypanothione reductase (TR) offered hints about the opportunity of synthesizing and testing diphenylsulfide derivatives with prolonged or branched polyamino side chains as putative TR inhibitors. The inhibition results within the synthesized series confirmed the main working hypothesis inspired by the molecular modeling study. The different compounds were tested in vitro on the enzyme and on Trypanosoma cruzi and Trypanosoma brucei trypomastigotes as well as in vivo in infected mice.

Animals↗
PubMed1988

Heterologous 5' flanking regions do not support in vitro template activity of a Drosophila melanogaster tRNA(Val3b) gene.

The 5' and 3' structure of a Drosophila tRNA(Val3b) gene was investigated to examine the defect which caused the extremely low in vitro transcription template activity of the gene. Recombinant genes were constructed linking 5' and 3' flanking regions from tRNA genes which were active in vitro templates (tRNA(Val4), tRNA(Arg), tRNA(Ser7)) to the tRNA(Val3b) gene. None of the recombinant genes were effective in vitro templates. The defect in tRNA(Val3b) was demonstrated to reside in the 5' flanking region of the gene and deletion analysis indicated that no specific transcription inhibitor sequence was present 5' to the gene. The data suggest that the effect of 5' flanking sequences on in vitro transcription of the tRNA(Val3b) gene requires a specific relationship between the tRNA gene and the flanking sequence.

Animals↗
PubMed1988

Sequences between the internal control regions of tRNAArg of Drosophila melanogaster influence stimulation of transcription of the 5' flanking DNA.

Recombinants between 5' deletion mutants of a tRNA(3bVal) gene which is inactive as an in vitro transcription template and a tRNAArg gene, which is an active in vitro template were made. The 5' flanking region of tRNA(Arg) including 36 nucleotides of the coding sequence of the gene stimulated transcription of the tRNA(3bVal), deleted to the +17 position, gene by over 50 fold. When the 5' flanking region of the tRNA(Arg) gene included 22 nucleotides of the coding sequence stimulation was reduced by a factor of 3. Thus the sequences between +22 and +36 of tRNA(Arg) are required to permit maximum stimulation of tRNA(3bVal) in vitro template activity.

Animals↗
PubMed1979

Aliphatic ketones are acetylcholinesterase inhibitors but not transition state analogs.

A number of C4--C9 aliphatic ketones are acetylcholinesterase (acetylcholine hydrolase, EC 3.1.1.7) inhibitors, with Ki values in the 0.7--5 mM range. Comparison to analogous substrates would suggest that these ketones are transition state analogs; e.g. 2-pentanone binds to the enzyme approx. 550 times more tightly than ethylacetate. However, a number of other criteria contradict this conclusions: (1) the binding is insensitive to ketone structure: isomeric ketones, cycloalkanones, and sterically hindered ketones have similar inhibitory potencies. (2) Analogous alcohols are also good inhibitors even though they cannot form hemiketals with the enzyme. (3) Representative ketones are relatively ineffective at blocking inactivation of the enzyme by methylsulfonyl fluoride, indicating that ketones do not bind principally at the hydrolytic site. (4) A competition experiment shows that binding of tetramethylammonium chloride excludes binding of 2-pentanone, suggesting that ketones bind to the anionic rather than the hydrolytic site. Thus, observation of tight binding relative to a substrate is not a sufficient criterion to establish that an inhibitor is a transition state analog.

Animals↗
PubMedDate not supplied

Stable blood lubricated hydrodynamic journal bearing with magnetic loading.

The Cleveland Clinic Foundation's Innovative Ventricular Assist System (IVAS) is distinguished by the use of a special hydrodynamic journal bearing to support the rotating assembly of the blood pump. In a permanently implanted blood pump, this bearing's characteristics of long life and high reliability are of paramount importance. In addition, this bearing's inherent self-pumping flow and the axial through flow caused by an imposed end-to-end pressure difference provides good washing, thus guarding against deposition. The basic computer analysis and preliminary testing results of this bearing were previously presented. This article reports the ongoing studies (both analytic and in vitro tests) on this innovative bearing as a component of the IVAS in general, with particular emphasis on its stable operating characteristics and reliability. The absence of vibration attributable to hydrodynamic instabilities related to the thick fluid film are both calculated and demonstrated during testing. A stable operating center of the rotor is shown to be inherent under magnetic side loads and resulting hydrodynamic bearing forces. A low shear as a result of large fluid-film thicknesses has been calculated, and low hemolysis has been shown by in vitro testing. Several unique design features of the bearing are believed to be responsible for this high level of performance.

Heart-Assist Devices↗
PubMedDate not supplied

The analysis, design, and testing of a blood lubricated hydrodynamic journal bearing.

The Cleveland Clinic Foundation's Innovative Ventricular Assist System (IVAS) uses a hydrodynamic journal bearing to support the rotating assembly of the blood pump. Bearing dimensions are chosen so that a stable film of lubricant develops and separates stationary and rotating pump surfaces during operation. This bearing type provides several advantages for a permanently implanted device, including essentially no wear for very long life and very high reliability, as well as a self pumping action that generates circumferential wash flow and thus lowers the risk of bearing associated deposition. However, these advantages are accompanied by design issues not encountered with typical journal bearing, such as low shear stress, bearing ends that are not at atmospheric pressure, and low radial bearing loads. To address these issues, several concepts for a hydrodynamic blood bearing were designed and analyzed using a special computer code to perform parametric studies. This design analysis code was developed to define optimum bearing performance under selected load and speed ranges and within practical tolerances. Results showed the range of dimensions and conditions over which an effective, reliable, blood lubricated journal bearing can be designed. Subsequent bench testing has validated the theoretical conclusions and shown this bearing type to be very robust in a blood pump application.

Biomechanical Phenomena↗