Simon K. Kearsley

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Similarity searches based on chemical descriptors have proven extremely useful in aiding large-scale drug screening. Typically an investigator starts with a "probe", a drug-like molecule with an interesting biological activity, and searches a database to find similar compounds. In some projects, however, the only known actives are peptides, and the(More)
We present a system, FLOG (Flexible Ligands Oriented on Grid), that searches a database of 3D coordinates to find molecules complementary to a macromolecular receptor of known 3D structure. The philosophy of FLOG is similar to that reported for DOCK [Shoichet, B.K. et al., J. Comput. Chem., 13 (1992) 380]. In common with that system, we use a match center(More)
How well can a QSAR model predict the activity of a molecule not in the training set used to create the model? A set of retrospective cross-validation experiments using 20 diverse in-house activity sets were done to find a good discriminator of prediction accuracy as measured by root-mean-square difference between observed and predicted activity. Among the(More)
Computational tools to search chemical structure databases are essential to finding leads early in a drug discovery project. Similarity methods are among the most diverse and most useful. We will present some lessons we have gathered over many years experience with in-house methods on several therapeutic problems. The effectiveness of any similarity method(More)
Distance constraints from two-dimensional NMR cross-relaxation data are used to derive a three-dimensional structure for acyl carrier protein from Escherichia coli. Several approaches to structure determination are explored. The most successful proves to be an approach that combines the early stages of a distance geometry program with energy minimization in(More)
Specially expanded databases containing three-dimensional structures are created to enhance the utility of docking methods to find new leads, i.e., active compounds of pharmacological interest. The expansion is based on the automatic generation of a set of maximally dissimilar conformations. The ligand receptor system of methotrexate and dihydrofolate(More)
Similarity searches using topological descriptors have proved extremely useful in aiding large-scale screening. We describe alternative forms of the atom pair (Carhart et al. J. Chem. Inf. Comput. Sci. 1985, 25, 64-73.) and topological torsion (Nilakantan et al. J. Chem. Inf. Comput. Sci. 1987, 27, 82-85.) descriptors that use physiochemical atom types.(More)
A new method SQ has been developed to provide fast, automatic, and objective pairwise three-dimensional molecular alignments. SQ uses an atom-based clique-matching step followed by an alignment scoring function that has been parametrized to recognize pharmacologically relevant atomic properties. Molecular alignments from SQ are consistent with known(More)