Searching for pharmacophoric patterns in databases of three-dimensional chemical structures

This paper provides an overview of the research that has been carried out in Sheffield over the last decade into searching techniques for databases of three-dimensional (3D) chemical structures. A 3D structure or query pattern is represented by a labelled graph, in which the nodes and the edges of the graph are used to represent atoms and the associated inter-atomic distances, respectively. The presence of a pharmacophore in each of the structures in a database can then be tested by means of a subgraph isomorphism algorithm, the computational requirements of which are minimized by the use of an initial screening procedure that eliminates the majority of the structures from the subgraph-isomorphism search. Analogous graph-based representation and searching methods can also be used with flexible 3D structures: in this case, the edges of the graphs represent inter-atomic distance ranges and a final conformational search needs to be carried out for those molecules that match the query pharmacophore in the subgraph-isomorphism search. The paper also reviews related work on the automatic identification of pharmacophoric patterns and on 3D similarity searching.     

Comparaisons des séquences d'ADN hautement répétées chez l'homme et diverses espèces de primates

Highly repeated DNA sequences from man, five other primate species and rat were compared using five restriction endonucleases. Calculations of a similarity index based on the mobility of various bands indicate that man, chimpanzee and baboons are very similar. The sequences of the genomes studied have apparently been reorganized during primate evolution.     

PDB-wide identification of physiological hetero-oligomeric assemblies based on conserved quaternary structure geometry

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The Concept of Additivity of Drug Combinations in the Case of Quantal Response

The concept of additivity of drug combinations is widely accepted in pharmacology and toxicology. Up to now, no general statistical methods to test that property are available. The present paper gives a mathematical formulation of additivity, a method to fit dose response surfaces under additivity assumption and a statistical test.     

Discovery of novel pathways for carbohydrate metabolism

Closing the gap between the increasing availability of complete genome sequences and the discovery of novel enzymes in novel metabolic pathways is a significant challenge. Here, we review recent examples of assignment of in vitro enzymatic activities and in vivo metabolic functions to uncharacterized proteins, with a focus on enzymes and metabolic pathways involved in the catabolism and biosynthesis of monosaccharides and polysaccharides. The most effective approaches are based on analyses of sequence-function space in protein families that provide clues for the predictions of the functions of the uncharacterized enzymes. As summarized in this Opinion, this approach allows the discovery of the catabolism of new molecules, new pathways for common molecules, and new enzymatic chemistries.     

Similarities between invaders and native species: Moving past Darwin's naturalization conundrum

Darwin's naturalization conundrum states that successful invaders must be closely related to native species to possess the traits to tolerate that environment, but distantly related enough to possess traits allowing exploitation of underutilized niches, thereby minimizing competition. Although influential, this hypothesis is based on several simplistic assumptions. In particular, the relationship among phylogenetic relatedness, similarity, and competition is more complex than assumed and changes with spatial and phylogenetic scale. Competitive interactions are determined by limiting similarity and trait hierarchies associated with separate traits. Successful invaders thus need to be similar to native species in some respects, but different in others. This combination of similarities and differences is unlikely to be conserved. Further, many invasive species are represented in their novel range by genotypes with extreme trait values or plasticity relative to the species mean. Selection for these genotypes may alter the similarity between invasive and native species, thus obscuring the relationship between competition and phylogenetic relatedness. As environmental filtering and competition often act on different spatial scales, approaches assessing how individual traits relate to invasion at these scales (species pools vs local community) may improve our understanding of the relationship between similarity and invasion.