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At least 37 records · Page 2Linked to original sources
PubMed2004

Predicting anti-HIV activity of 2,3-diaryl-1,3-thiazolidin-4-ones: computational approach using reformed eccentric connectivity index.

The eccentric connectivity index, which has recently been employed successfully for the development of numerous mathematical models for the prediction of biological activities of diverse nature, has been reformed to overcome its limitations caused by degeneracy and insensitivity towards heteroatoms. The reformed eccentric connectivity index, termed the eccentric connectivity topochemical index, overcomes the limitations of the eccentric connectivity index by exhibiting very low degeneracy and displaying sensitivity to both the presence and relative position of heteroatoms without compromizing the discriminating power of the eccentric connectivity index. The relationship of the eccentric connectivity topochemical index, eccentric connectivity index and Wiener's index with regard to the anti-HIV activity of 2, 3-diaryl-1, 3-thiazolidin-4-one derivatives was subsequently investigated. The values of the eccentric connectivity topochemical index, the eccentric connectivity index and Wiener's index of each of 31 analogues comprizing the data set were computed using in-house computer program. Resultant data was analyzed and suitable models developed after identification of active ranges. Subsequently, each derivative was assigned a biological activity using these models, which was then compared with the reported anti-HIV activity. The accuracy of prediction using these models was found to vary from 81 to 90%. The proposed index offers a vast potential for virtual screening of combinatorial libraries, structure property/activity studies and drug design. [figure]. Basic structure of 2,3-diaryl-1, 3-thiazoidin-4-ones.

Anti-HIV Agents↗
PubMed1979

Formal education and intellectual functioning in the immigrant Cuban elderly.

Formal educational experience during childhood and adolescence is an important modifier of intellectual functioning in North American elderly populations. The culture-independence of this relationship was examined with 31 immigrant Cuban elderly men and women who received their education in Cuba. The amount of formal education was significantly related to performance on measures of classification, combinatorial analysis (males only), hypothesis testing, and matrices. An index of fluid intelligence (matrices) also was significantly related to performance on the classification and hypothesis testing tasks. All participants conserved both liquid and mass, thus showing no regression on these two concerete operational tasks.

Aged↗
PubMedDate not supplied

QSAR comparative study of Wiener descriptors for weighted molecular graphs.

Quantitative structure-property relationship (QSPR) and quantitative structure-activity relationship (QSAR) studies use statistical models to compute physical, chemical, or biological properties of a chemical substance from its molecular structure, encoded in a numerical form with the aid of various descriptors. Structural indices derived from molecular graph matrices represent an important group of descriptors used in QSPR and QSAR models; recently, their utilization was extended to molecular similarity and diversity, in database mining and virtual screening of combinatorial libraries. Initially defined from the distance matrix, the Wiener index W was the source of novel graph descriptors derived from recently proposed molecular matrices and of the Wiener graph operator. In this work we present a comparative study of several Wiener-type descriptors computed for vertex- and edge-weighted molecular graphs, corresponding to organic compounds with heteroatoms and multiple bonds. The acute toxicities toward Tetrahymena pyriformis of 47 nitrobenzenes are modeled with multilinear regression equations, using as structural descriptors the hydrophobicity (corrected for ionization) and various Wiener-type indices, with better results than a comparative molecular field analysis model.

Journal Article↗
PubMedDate not supplied

Computing wiener-type indices for virtual combinatorial libraries generated from heteroatom-containing building blocks.

The expensive and time-consuming process of drug lead discovery is significantly accelerated by efficiently screening molecular libraries with a high structural diversity and selecting subsets of molecules according to their similarity toward specific collections of active compounds. To characterize the molecular similarity/diversity or to quantify the drug-like character of compounds the process of screening virtual and synthetic combinatorial libraries uses various classes of structural descriptors, such as structure keys, fingerprints, graph invariants, and various topological indices computed from atomic connectivities or graph distances. In this paper we present efficient algorithms for the computation of several distance-based topological indices of a molecular graph from the distance invariants of its subgraphs. The procedures utilize vertex- and edge-weighted molecular graphs representing organic compounds containing heteroatoms and multiple bonds. These equations offer an effective way to compute for weighted molecular graphs the Wiener index, even/odd Wiener index, and resistance-distance index. The proposed algorithms are especially efficient in computing distance-based structural descriptors in combinatorial libraries without actually generating the compounds, because only distance-based indices of the building blocks are needed to generate the topological indices of any compound assembled from the building blocks.

Journal Article↗
PubMed2005

All-cis cyclic peptides.

Amide bonds -NH-CO- preferentially exist in trans conformations, the cis conformation being thermodynamically unfavored with respect to the trans by about 2 kcal/mol. Yet, the main reason most proteins or peptides cannot be made from cis-peptide plaques only lies in that connecting them into open chains appears to be sterically impracticable. It is possible, however, to build all-cis cyclic peptides in which all cis-plaques are efficiently locked. The present work examines, through quantum calculations, the structural and energetic issues associated with these peculiar arrangements. Systematic exploration at DFT-B3LYP level of the potential-energy surfaces for all-cis cyclopolyglycines cG(n)(c) (n = 2-10,15), and to a lesser extent, for all-cis cyclopolyalanines and all-cis cyclopolyphenylalanines confirms that all these structures are true minima. Optimal ring size occurs around eight peptide units, resulting in planar cG7(c), cG8(c), and cG9(c). In smaller systems, the ring strain is relieved through nonplanar cup-like distortions, particularly in cG6(c). From 10 peptide units and beyond, the ring framework distorts into a saddle-edge shape. These molecules disclose some molecular flexibility, as combinatorial tilting of the plaques may give sets of minima close in energy. Indexes based on isodesmic reactions are used to estimate the energy for joining all-cis or all-trans plaques into cyclic peptides. One of them, the mean plaque-junction energy (MPJE) suggests that within sensible sizes from six peptide units and beyond, all-cis plaque association is almost equally favorable as all-trans one. The frame of radiating cis-amide bonds can be considered as defining a new kind of peptidic material, endowed with specific self-assembling properties.

Crystallography, X-Ray↗
PubMed2006

Systems biology and combination therapy in the quest for clinical efficacy.

Combinatorial control of biological processes, in which redundancy and multifunctionality are the norm, fundamentally limits the therapeutic index that can be achieved by even the most potent and highly selective drugs. Thus, it will almost certainly be necessary to use new 'targeted' pharmaceuticals in combinations. Multicomponent drugs are standard in cytotoxic chemotherapy, but their development has required arduous empirical testing. However, experimentally validated numerical models should greatly aid in the formulation of new combination therapies, particularly those tailored to the needs of specific patients. This perspective focuses on opportunities and challenges inherent in the application of mathematical modeling and systems approaches to pharmacology, specifically with respect to the idea of achieving combinatorial selectivity through use of multicomponent drugs.

Drug Therapy, Combination↗
PubMed2004

An optimal structure-discriminative amino acid index for protein fold recognition.

Identifying the fold class of a protein sequence of unknown structure is a fundamental problem in modern biology. We apply a supervised learning algorithm to the classification of protein sequences with low sequence identity from a library of 174 structural classes created with the Combinatorial Extension structural alignment methodology. A class of rules is considered that assigns test sequences to structural classes based on the closest match of an amino acid index profile of the test sequence to a profile centroid for each class. A mathematical optimization procedure is applied to determine an amino acid index of maximal structural discriminatory power by maximizing the ratio of between-class to within-class profile variation. The optimal index is computed as the solution to a generalized eigenvalue problem, and its performance for fold classification is compared to that of other published indices. The optimal index has significantly more structural discriminatory power than all currently known indices, including average surrounding hydrophobicity, which it most closely resembles. It demonstrates >70% classification accuracy over all folds and nearly 100% accuracy on several folds with distinctive conserved structural features. Finally, there is a compelling universality to the optimal index in that it does not appear to depend strongly on the specific structural classes used in its computation.

Algorithms↗
PubMedDate not supplied

Synthesis and screening of an indexed motif-library containing non-proteinogenic amino acids.

In an effort to increase the probability of finding novel peptides in resin-bound combinatorial libraries displaying affinity to various macromolecular targets, we increased the diversity of a solid-phase library considerably by synthesizing multiple structures on each bead - a motif-library - including 45 building blocks. The building blocks consist of L-aa, D-aa and eight hydrophobic non-proteinogenic alpha-amino acids. A library with the format O-Z0-1-O-Z0-1-O-XX-resin was synthesized giving the four motifs OOOXX, OZOOXX, OOZOXX, OZOZOXX corresponding to 364.500 different motifs (45(3) x 4 theoretical combinations). The positions O are defined amino acids while Z represents three mixtures pi, omega, phi, where pi is a mixture of polar and charged residues, omega is a mixture of aliphatic residues and phi is a mixture of aromatic residues. X represents a mixture of all 45 residues. The library was screened with the macromolecular target streptavidin which served as a model receptor. Binding peptides were sequenced by microsequencing. We included small amounts of norvaline and norleucine in the library, which served as index residues to be able to distinguish between LD-amino acids and other residues with the same retention time in the HPLC system. Beads that interact with the receptor were found, and the binding motifs that appeared had no homology to known binding motifs found in either L-aa or D-aa libraries, instead motifs with the non-proteinogenic residues L-phenylglycine, O-benzyl-L-hydroxyproline and O-benzyl-L-tyrosine dominated. The novel peptides inhibit binding of biotin to streptavidin but do not bind to avidin, and the affinity is higher than the peptides found in linear all L-aa peptide libraries.

Amino Acids↗
PubMed1999

Zones of low entropy in genomic sequences.

We consider the problem of detecting regions having low entropy in DNA sequences, which is a particular case of searching for dos-DNA zones. The entropy is measured in linear time as the number of distinct segments occurring in the regions. As a consequence, we are able to determine regions containing a small number of repetitions of long segments or a large number of repetitions of short segments. The method provides an index on sequences that is applied to compare them without any alignment. Comparisons extract regions having similar combinatorial features that would not have been found by standard alignment methods. The present methodology is applied to Saccharomyces cerevisiae yeast chromosomes to show what the approach is able to produce.

Base Sequence↗
PubMed2006

Expanding the therapeutic index of radiation therapy by combining in situ gene therapy in the treatment of prostate cancer.

The advances in radiotherapy (3D-CRT, IMRT) have enabled high doses of radiation to be delivered with the least possible associated toxicity. However, the persistence of cancer (local recurrence after radiotherapy) despite these increased doses as well as distant failure suggesting the existence of micro-metastases, especially in the case of higher risk disease, have underscored the need for continued improvement in treatment strategies to manage local and micro-metastatic disease as definitively as possible. This has prompted the idea that an increase in the therapeutic index of radiotherapy might be achieved by combining it with in situ gene therapy. The goal of these combinatorial therapies is to maximize the selective pressure against cancer cell growth while minimizing treatment-associated toxicity. Major efforts utilizing different gene therapy strategies have been employed in conjunction with radiotherapy. We reviewed our and other published clinical trials utilizing this combined radio-genetherapy approach including their associated pre-clinical in vitro and in vivo models. The use of in situ gene therapy as an adjuvant to radiation therapy dramatically reduced cell viability in vitro and tumor growth in vivo. No significant worsening of the toxicities normally observed in single-modality approaches were identified in Phase I/II clinical studies. Enhancement of both local and systemic T-cell activation was noted with this combined approach suggesting anti-tumor immunity. Early clinical outcome including biochemical and biopsy data was very promising. These results demonstrate the increased therapeutic efficacy achieved by combining in situ gene therapy with radiotherapy in the management of local prostate cancer. The combined approach maximizes tumor control, both local-regional and systemic through radio-genetherapy induced cytotoxicity and anti-tumor immunity.

Animals↗
PubMed2005

Optimization of alkaline protease production by Bacillus sp. using Taguchi methodology.

Optimization of alkaline protease production parameters by Bacillus sp. was investigated using Taguchi methodology. The pH of the medium was observed to be the most significant factor among all selected optimization parameters at an individual level. The combinatorial influence of least significant factors, inoculum level and salt solution concentration (at the individual level), resulted in an interacting severity index of 76%, suggesting their interactive role in the regulation of protease production in this microbial species. Protease production could be improved more than 100% with Taguchi's optimized conditions of the medium composition by this microorganism.

Analysis of Variance↗
PubMedDate not supplied

Nursing classification systems: necessary but not sufficient for representing "what nurses do" for inclusion in computer-based patient record systems.

Our premise is that from the perspective of maximum flexibility of data usage by computer-based record (CPR) systems, existing nursing classification systems are necessary, but not sufficient, for representing important aspects of "what nurses do." In particular, we have focused our attention on those classification systems that represent nurses' clinical activities through the abstraction of activities into categories of nursing interventions. In this theoretical paper, we argue that taxonomic, combinatorial vocabularies capable of coding atomic-level nursing activities are required to effectively capture in a reproducible and reversible manner the clinical decisions and actions of nurses, and that, without such vocabularies and associated grammars, potentially important clinical process data is lost during the encoding process. Existing nursing intervention classification systems do not fulfill these criteria. As background to our argument, we first present an overview of the content, methods, and evaluation criteria used in previous studies whose focus has been to evaluate the effectiveness of existing coding and classification systems. Next, using the Ingenerf typology of taxonomic vocabularies, we categorize the formal type and structure of three existing nursing intervention classification system--Nursing Interventions Classification, Omaha System, and Home Health Care Classification. Third, we use records from home care patients to show examples of lossy data transformation, the loss of potentially significant atomic data, resulting from encoding using each of the three systems. Last, we provide an example of the application of a formal representation methodology (conceptual graphs) which we believe could be used as a model to build the required combinatorial, taxonomic vocabulary for representing nursing interventions.

Abstracting and Indexing↗
PubMed2005

Can topological indices transmit information on properties but not on structures?

A survey of several topological indices (TIs) is provided according to the nature (integers or real numbers) of the local vertex invariants (LOVIs) and of the resulting molecular descriptor (TI). The 1st generation TIs such as the Wiener index when both the LOVIs and the TI are integers have a very high degeneracy. This fact can become an asset for the problem under discussion: when confronted with the "inverse problem" (reverse engineering) such indices lead to a combinatorial explosion of possible solutions. On the other extreme, TIs with very low degeneracy may also offer the possibility to transmit information on properties but not on structures, because they may be too difficult to lend themselves to reverse engineering in a reasonable amount of time. Several such indices are discussed: the novel second-generation index G (derived from the average distance-based connectivity index J in order to include a dependence on graph size and cyclicity), and third-generation indices such as the triplet TI denoted by DN2S(4) or the Kier-Hall index TOTOP. The intercorrelation of these indices is discussed: G is almost linearly-correlated with DN2S(4), and shows a different type of correlation with TOTOP.

Alkanes↗
PubMed2005

Identification of a novel antifungal nonapeptide generated by combinatorial approach.

It is becoming clear that antimicrobial peptides are important components of the innate defences of all species of life. They kill very rapidly, do not easily select resistant mutants and are synergistic with potentially toxic conventional therapeutic agents against microbes. This paper describes an attempt to expand a lead hexapeptide motif synthesized through combinatorial approach. A cationic peptide H-Arg-Trp-Trp-Arg-D-Trp-D-Phe-Ile-D-Phe-His-NH2 was found to be active with a therapeutic index of >17. I was proposed that the combination of peptide with known antifungal agents may identify synergistic combinations that would ideally reduce the dosage of conventional antifungals as well as their associated toxicity. Nine different pathogenic strains and species of Candida and two of Cryptococcus neoformans were employed in chequerboard method and in time kill assays to evaluate the synergistic effect of the lead peptide in combination with amphotericin B, 5-flucytosine, ketoconazole and fluconazole. We found synergistic interaction between the peptide and all four drugs against Cryptococcus isolates whilst both synergistic and additive combinations occurred when Candida isolates were used.

Amino Acid Motifs↗
PubMed2001

Quantitative structure-property relationships generated with optimizable even/odd Wiener polynomial descriptors.

Chemical structures of organic compounds are characterized numerically by a variety of structural descriptors, one of the earliest and most widely used being the Wiener index W, derived from the interatomic distances in a molecular graph. Extensive use of distance-based structural descriptors or topological indices has been made in QSPR and QSAR models, drug design, toxicology, virtual screening of combinatorial libraries, similarity and diversity assessment. Novel topological indices are introduced representing a partitioning of the Wiener polynomial based on counts of even and odd molecular graph distances. During the QSAR/QSPR modeling process the variables of the even and odd power functions are optimized in order to offer an improved mapping of the investigated property. These novel topological indices are tested in QSPR models for the boiling temperature, molar heat capacity, standard Gibbs energy of formation, vaporization enthalpy, refractive index, and density of alkanes. In many cases, the even/odd Wiener polynomial indices proposed here give notably improved correlations or suggest simpler QSPR models.

Chemical Phenomena↗
PubMed2000

Molecular dataset diversity indices and their applications to comparison of chemical databases and QSAR analysis

A new mutual molecular dataset diversity index (MMDDI), individual molecular dataset diversity index (IMDDI), and volume ratio (VR) are proposed to assess molecular dataset diversity. MMDDI and IMDDI can serve as valuable instruments for selecting monomer pools for combinatorial synthesis and in decision making about acquiring new databases. MMDDI can also be used as one of the criteria to estimate the quality of quantitative structure-activity relationship (QSAR) models aimed at the prediction of biological activities. The indices can be calculated directly from molecular descriptor values. The procedures applied for MMDDI and IMDDI calculations allow one to automatically compile lists of compounds, which can simplify molecular diversity analyses and database searching. The information can also be used for forming training and test sets in QSAR analysis.

Journal Article↗
PubMed1997

Manic indices on the Rorschach.

This study examined signs of mania on the Rorschach, specifically whether manic inpatients (n = 24) produce different thematic content and thought disorder than comparison groups of paranoid schizophrenic (n = 27) and schizoaffective (n = 25) inpatients. Rorschach protocols were scored by a trained rater for the Thought Disorder Index and the Schizoid-Affective Rating Scale. Results indicated that all 3 groups had moderate levels of thought disorder, but the manic inpatients produced significantly more combinatory thinking and affective content responses than the other 2 groups. The paranoid schizophrenic and schizoaffective patients did not produce significantly more schizoid content and were not different on any other types of thought disorder than the manic patients. These findings are discussed in terms of the contribution of thought disorder and affective thematic content in making the diagnosis of mania on the Rorschach.

Adult↗
PubMed2026

Comparative Effectiveness of Pharmacogenomics for Treatment of Depression.

PURPOSE/BACKGROUND: Pharmacogenomics (PGx), or the use of genetic information to assess drug-gene interactions, is an important step toward precision medicine. It is unclear if clinician use of PGx yields better outcomes for their patients. This study compared the effectiveness of combinatorial PGx-guided plus guideline-informed treatment (PGx+GIT) with guideline-informed treatment (GIT) alone to improve well-being in individuals with major depressive disorder. METHODS/PROCEDURES: Eligible participants (N=201) were randomized to PGx+GIT or GIT alone. PGx was measured with the proprietary GeneSight combinatorial test. PGx+GIT participant clinicians received test results within 2 business days to inform decisions about medication changes. Participants completed the World Health Organization Well-Being Index (WHO-5), Patient Health Questionnaire (PHQ-9), and PROMIS Profile physical functioning and social roles and activity domains every 2 weeks for 2 months and then every 2 months for the remaining 10 months. Monthly medication changes operationalized as necessary clinical adjustments were tracked with the medication recommendation tracking form. FINDINGS/RESULTS: Both groups improved average well-being over the 12-month study period (model-based change in WHO-5 per log (week) [95% CI]: 4.1 [3.3, 5.0] PGx+GIT and 4.8 [4.0, 5.5] GIT). PGx+GIT did not result in superior improvement in well-being (model-based difference [95% CI]: -0.6 [-1.8, 0.5], P =0.270), or any secondary outcomes. The effect of randomized treatment on well-being was not moderated by depression severity, number of previous failed medications for major depressive disorder, or presence of a comorbid condition. IMPLICATIONS/CONCLUSIONS: These data suggest PGx+GIT was not superior to GIT alone, possibly due to a ceiling effect of GIT, or PGx did not yield better results.

Humans↗