Biomedical subjects

Jonathan Bard

Publications and source records attributed to Jonathan Bard.

8 recordsLinked to original sources

PubMed2006

Acylguanidines as small-molecule beta-secretase inhibitors.

BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Abeta, which aggregates leading to plaque deposits implicated in Alzheimer's disease. We have identified small-molecule acylguanidine inhibitors of BACE1. Crystallographic studies show that these compounds form unique hydrogen-bonding interactions with the catalytic site aspartic acids and stabilize the protein in a flap-open conformation. Structure-based optimization led to the identification of potent analogs, such as 10d (BACE1 IC(50) = 110 nM).

Amyloid Precursor Protein Secretases↗

PubMed2006

A novel approach to identifying beta-secretase inhibitors: bis-statine peptide mimetics discovered using structure and spot synthesis.

Beta-secretase 1 (BACE1) is an aspartic protease believed to play a critical role in Alzheimer's disease. Inhibitors of this enzyme have been designed by incorporating the non-cleavable hydroxyethylene and statine isosteres into peptides corresponding to BACE1 substrate sequences. We sought to develop new methods to quickly characterize and optimize inhibitors based on the statine core. Minimal sequence requirements for binding were first established using both crystallography and peptide spot synthesis. These shortened peptide inhibitors were then optimized by using spot synthesis to perform iterative cycles of substitution and deletion. The present study resulted in the identification of novel "bis-statine" inhibitors shown by crystallography to have a unique binding mode. Our results demonstrate the application of peptide spot synthesis as an effective method for enhancing peptidomimetic drug discovery.

Amino Acid Sequence↗

PubMed2005

An ontology for cell types.

We describe an ontology for cell types that covers the prokaryotic, fungal, animal and plant worlds. It includes over 680 cell types. These cell types are classified under several generic categories and are organized as a directed acyclic graph. The ontology is available in the formats adopted by the Open Biological Ontologies umbrella and is designed to be used in the context of model organism genome and other biological databases. The ontology is freely available at http://obo.sourceforge.net/ and can be viewed using standard ontology visualization tools such as OBO-Edit and COBrA.

Animals↗

PubMed2004

COBrA: a bio-ontology editor.

COBrA is a Java-based ontology editor for bio-ontologies that distinguishes itself from other editors by supporting the linking of concepts between two ontologies, and providing sophisticated analysis and verification functions. In addition to the Gene Ontology and Open Biology Ontologies formats, COBrA can import and export ontologies in the Semantic Web formats RDF, RDFS and OWL.

Cell Physiological Phenomena↗

PubMed2004

Human-Mouse Gene Searcher: a tool to assist discovery of malformation-associated genes by using phenotype databases.

UNLABELLED: An open-access World Wide Web application has been developed which enables the cross-linking of anatomical data on the phenotypic manifestations of human and mouse malformation syndromes to data on gene function and/or expression patterns in the mouse GXD database. Ultimately, the system has been designed to assist biologists in the process of discovering hitherto unidentified malformation genes. More specifically, it facilitates search from the phenotypic level. AVAILABILITY: The application and further information is available at http://genetics.ich.ucl.ac.uk/linksearchtool.

Animals↗

PubMed2004

Evaluation of fluorescence-based thermal shift assays for hit identification in drug discovery.

The fluorescence-based thermal shift assay is a general method for identification of inhibitors of target proteins from compound libraries. Using an environmentally sensitive fluorescent dye to monitor protein thermal unfolding, the ligand-binding affinity can be assessed from the shift of the unfolding temperature (Delta Tm) obtained in the presence of ligands relative to that obtained in the absence of ligands. In this article, we report that the thermal shift assay can be conducted in an inexpensive, commercially available device for temperature control and fluorescence detection. The binding affinities obtained from thermal shift assays are compared with the binding affinities measured by isothermal titration calorimetry and with the IC(50) values from enzymatic assays. The potential pitfalls in the data analysis of thermal shift assays are also discussed.

Amyloid Precursor Protein Secretases↗

PubMed2004

Synthesis and SAR of bis-statine based peptides as BACE 1 inhibitors.

A new series of bis-statine based peptidomimetic inhibitors of human beta-secretase (BACE 1) was developed by structure-based modification of the three regions to the initial lead 3: an N-terminus, a central bis-statine core, and a C-terminus. Introduction of a 4-aminomethylbenzoic acid on the C-terminus resulted in a potent BACE 1 inhibitor with an IC50 value of 21 nM. The general requirements for the optimal substrate-enzyme interaction are disclosed herein.

4-Aminobenzoic Acid↗

PubMed2003

Ontologies: Formalising biological knowledge for bioinformatics.

An ontology is a domain of knowledge structured through formal rules so that it can be interpreted and used by computers. Ontologies are becoming increasingly important in bioinformatics because they can be linked to the information in databases and their knowledge then used to query the databases. Typical examples in current use are the Gene Ontology, which incorporates much of our knowledge about gene products, and ontologies of developmental anatomy, which, for example, facilitate tissue-based queries to gene expression databases both textually and spatially. This article considers the production, formulation and types of bio-ontologies together with the reasons why they are so useful.

Animals↗