David A. Cosgrove

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By identifying every pair of molecules that differ only by a particular, well-defined, structural transformation in a database of measured properties and computing the corresponding change in property, we obtain an overview of the effect that structural change has upon the property and set an expectation for what will happen when that transformation is(More)
The combination of 3D pharmacophore fingerprints and the support vector machine classification algorithm has been used to generate robust models that are able to classify compounds as active or inactive in a number of G-protein-coupled receptor assays. The models have been tested against progressively more challenging validation sets where steps are taken(More)
Similarity-based methods for virtual screening are widely used. However, conventional searching using 2D chemical fingerprints or 2D graphs may retrieve only compounds which are structurally very similar to the original target molecule. Of particular current interest then is scaffold hopping, that is, the ability to identify molecules that belong to(More)
A virtual screen of a subsection of the AstraZeneca compound collection was performed for checkpoint kinase-1 (Chk-1 kinase) using a knowledge-based strategy. This involved initial filtering of the compound collection by application of generic physical properties followed by removal of compounds with undesirable chemical functionality. Subsequently, a 3-D(More)
Approaches to the design of libraries for fragment screening are illustrated with reference to a 20 k generic fragment screening library and a 1.2 k generic NMR screening library. Tools and methods for library design that have been developed within AstraZeneca are described, including Foyfi fingerprints and the Flush program for neighborhood(More)
A novel shape-based method has been developed for overlaying a series of molecule surfaces into a common reference frame. The surfaces are represented by a set of circular patches of approximately constant curvature. Two molecules are overlaid using a clique-detection algorithm to find a set of patches in the two surfaces that correspond, and overlaying the(More)
The program SLASH, which is designed to enable large numbers of compounds to be analysed in terms of the functional groups they contain, is described. The usefulness of the groups for analysing the activities of compounds tested in high-throughput biological screens is investigated. The functional group fragments are also studied as a means of determining(More)
Chemical databases are routinely clustered, with the aim of grouping molecules which share similar structural features. Ideally, medicinal chemists are then able to browse a few representatives of the cluster in order to interpret the shared activity of the cluster members. However, when molecules are clustered using fingerprints, it may be difficult to(More)
The pharmacophore hypothesis plays a central role in both the design and optimization of drug-like ligands. Pharmacophore patterns are invoked to explain the binding affinity of ligands and to enable the design of chemically distinct scaffolds that show affinity for a protein target of interest. The importance of pharmacophores in rationalizing ligand(More)
Two methods are described for biasing conformational search during pharmacophore elucidation using a multiobjective genetic algorithm (MOGA). The MOGA explores conformation on-the-fly while simultaneously aligning a set of molecules such that their pharmacophoric features are maximally overlaid. By using a clique detection method to generate overlays of(More)