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G Harper

Publications and source records attributed to G Harper.

88 records · Page 5Linked to original sources
PubMedDate not supplied

Prediction of biological activity for high-throughput screening using binary kernel discrimination.

High-throughput screening has made a significant impact on drug discovery, but there is an acknowledged need for quantitative methods to analyze screening results and predict the activity of further compounds. In this paper we introduce one such method, binary kernel discrimination, and investigate its performance on two datasets; the first is a set of 1650 monoamine oxidase inhibitors, and the second a set of 101 437 compounds from an in-house enzyme assay. We compare the performance of binary kernel discrimination with a simple procedure which we call "merged similarity search", and also with a feedforward neural network. Binary kernel discrimination is shown to perform robustly with varying quantities of training data and also in the presence of noisy data. We conclude by highlighting the importance of the judicious use of general pattern recognition techniques for compound selection.

Algorithms↗
PubMedDate not supplied

Molecular complexity and its impact on the probability of finding leads for drug discovery.

Using a simple model of ligand-receptor interactions, the interactions between ligands and receptors of varying complexities are studied and the probabilities of binding calculated. It is observed that as the systems become more complex the chance of observing a useful interaction for a randomly chosen ligand falls dramatically. The implications of this for the design of combinatorial libraries is explored. A large set of drug leads and optimized compounds is profiled using several different properties relevant to molecular recognition. The changes observed for these properties during the drug optimization phase support the hypothesis that less complex molecules are more common starting points for the discovery of drugs. An extreme example of the use of simple molecules for directed screening against thrombin is provided.

Drug Design↗
PubMedDate not supplied

The reduced graph descriptor in virtual screening and data-driven clustering of high-throughput screening data.

Virtual screening and high-throughput screening are two major components of lead discovery within the pharmaceutical industry. In this paper we describe improvements to previously published methods for similarity searching with reduced graphs, with a particular focus on ligand-based virtual screening, and describe a novel use of reduced graphs in the clustering of high-throughput screening data. Literature methods for reduced graph similarity searching encode the reduced graphs as binary fingerprints, which has a number of issues. In this paper we extend the definition of the reduced graph to include positively and negatively ionizable groups and introduce a new method for measuring the similarity of reduced graphs based on a weighted edit distance. Moving beyond simple similarity searching, we show how more flexible queries can be built using reduced graphs and describe a database system that allows iterative querying with multiple representations. Reduced graphs capture many important features of ligand-receptor interactions and, in conjunction with other whole molecule descriptors, provide an informative way to review HTS data. We describe a novel use of reduced graphs in this context, introducing a method we have termed data-driven clustering, that identifies clusters of molecules represented by a particular whole molecule descriptor and enriched in active compounds.

Journal Article↗
PubMedDate not supplied

Simulated blood levels of CF3I in personnel exposed during its release from an F-15 jet engine nacelle and during intentional inhalation.

Of the agents under consideration for protecting unoccupied areas from fire, CF3I (trifluoroiodomethane) has physicochemical properties that give it potential as a "drop-in" replacement for halon 1301. One of the issues concerning the use of CF3I is the potential hazard to ground crews should an inadvertent discharge occur while workers are in or near an engine nacelle. A discharge test of CF3I was conducted on an F-15A jet to record CF3I concentration time histories at locations near the aircraft. The conditions of the discharges simulated an inadvertent ground discharge with the engine nacelle doors open and also with the doors closed. The use of three types of gas analysis instrumentation allowed gas sampling from several locations during the discharge tests. Concentrations measured at selected sensor locations were used as the input to a physiologically based pharmacokinetic model to simulate blood levels that would be attained by individuals inhaling CF3I at sensor locations. Blood levels reached during these exposures were compared with the blood level associated with the lowest observable adverse effect level (LOAEL) for cardiac sensitization to evaluate the possibility of safe egress. The highest blood concentrations simulated were twice the target blood concentration associated with cardiac sensitization. However, simulated blood concentrations of subjects who actually inhaled CF3I reached levels that were 100 times the target level without reported adverse effect. Thus, actual human data may supersede the use of the cardiac sensitization LOAEL obtained from animal studies.

Aircraft↗
PubMedDate not supplied

Child and adolescent psychiatry: toward the twenty-first century.

The history of child and adolescent psychiatry is reviewed, from its beginning in the Hull House movement in Chicago a century ago through subsequent social and scientific transformations. The field's relationships to academic medicine, to progress in the basic sciences, and to child advocacy are described. Current challenges to the field, including the gaps in and barriers to care, the emergence of for-profit enterprises, and the lack of consensus regarding health care regulation, are discussed in terms of the evolving social mission of the profession. Priorities for the next century are identified.

Adolescent Psychiatry↗