Valerie J. Gillet

Three-Dimensional Pharmacophore Methods in Drug Discovery

Andrew R. Leach,* ) Valerie J. Gillet, Richard A. Lewis, and Robin Taylor Computational and Structural Chemistry, GlaxoSmithKline Research & Development, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Department of Information Studies, University of Sheffield, Regent Court, 211 Portobello Street, Sheffield S1 4DP, U.K., Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland, and Taylor Cheminformatics Software, 54 Sherfield Avenue, Rickmansworth, Herts WD3 1NL, U.K.

The Effectiveness of Reactant Pools for Generating Structurally-Diverse Combinatorial Libraries

Current approaches to the design of combinatorial libraries assume that structural diversity in the reactant pools corresponds to structural diversity in the combinatorial libraries that result from reacting these pools together. In experiments with three different published libraries, dissimilarity-based compound selection (DBCS) is applied at two levels. First, the DBCS algorithm is applied at the reactant level, a library is built, and its diversity is measured. Second, the DBCS algorithm is applied to the full set of products generated by enumeration of all the reactants and the diversity of the subset is measured. Results show that reactant-based selection, which attempts to maximize diversity in the pools, results in noticeably less diverse libraries than if the selection is performed at the product level. Experiments are reported to estimate the upperbound to diversity achievable using DBCS, and it appears that DBCS is very effective at finding maximally diverse subsets. However, applying DBCS sele...

Selecting Combinatorial Libraries to Optimize Diversity and Physical Properties

The program SELECT is presented for the design of combinatorial libraries. SELECT is based on a genetic algorithm with a multi-objective fitness function. Any number of objectives can be included, provided that they can be readily calculated. Typically, the objectives would be to maximize structural diversity while ensuring that the compounds in the library have “drug-like” properties. In the examples given, structural diversity is measured using Daylight fingerprints as descriptors and either the normalized sum of pairwise dissimilarities, calculated with the cosine coefficient, or the average nearest neighbor distance, calculated with the Tanimoto coefficient, as the measure of diversity. The objectives are specified at run time. Combinatorial libraries are selected by analyzing product space, which gives significant advantages over methods that are based on analyzing reactant space. SELECT can also be used to choose an optimal configuration for a multicomponent library. The performance of SELECT is dem...

SPROUT: recent developments in the de novo design of molecules.

SPROUT is a computer program for constrained structure generation. It is designed to generate molecules for a range of applications in molecular recognition. The program uses a number of approximations that enable a wide variety of diverse structures to be generated. Practical use of the program is demonstrated in two examples. The first demonstrates the ability of the program to generate candidate inhibitors for a receptor site of known 3D structure, specifically the GDP binding site of p21. In the second example, structures are generated to fit a pharmacophore hypothesis that models morphine agonists.

Review of ring perception algorithms for chemical graphs

Current ring perception algorithms for use on chemical graphs concentrate on processing specific structures. In this review, the various published ring perception algorithms are classified according to the initial ring set obtained, and each algorithm or method of perception is described in detail. The final ring sets obtained are discussed in terms of their suitability for use in representing the ring systems in structurally explicit parts of generic chemical structures.

Similarity searching using reduced graphs

Reduced graphs provide summary representations of chemical structures. In this work, the effectiveness of reduced graphs for similarity searching is investigated. Different types of reduced graphs are introduced that aim to summarize features of structures that have the potential to form interactions with receptors while retaining the topology between the features. Similarity searches have been carried out across a variety of different activity classes. The effectiveness of the reduced graphs at retrieving compounds with the same activity as known target compounds is compared with searching using Daylight fingerprints. The reduced graphs are shown to be effective for similarity searching and to retrieve more diverse active compounds than those found using Daylight fingerprints; they thus represent a complementary similarity searching tool.

Lead Optimization Using Matched Molecular Pairs: Inclusion of Contextual Information for Enhanced Prediction of hERG Inhibition, Solubility, and Lipophilicity

Previous studies of the analysis of molecular matched pairs (MMPs) have often assumed that the effect of a substructural transformation on a molecular property is independent of the context (i.e., the local structural environment in which that transformation occurs). Experiments with large sets of hERG, solubility, and lipophilicity data demonstrate that the inclusion of contextual information can enhance the predictive power of MMP analyses, with significant trends (both positive and negative) being identified that are not apparent when using conventional, context-independent approaches.

A comparison of the pharmacophore identification programs: Catalyst, DISCO and GASP

Three commercially available pharmacophore generation programs, Catalyst/HipHop, DISCO and GASP, were compared on their ability to generate known pharmacophores deduced from protein-ligand complexes extracted from the Protein Data Bank. Five different protein families were included Thrombin, Cyclin Dependent Kinase 2, Dihydrofolate Reductase, HIV Reverse Transcriptase and Thermolysin. Target pharmacophores were defined through visual analysis of the data sets. The pharmacophore models produced were evaluated qualitatively through visual inspection and according to their ability to generate the target pharmacophores. Our results show that GASP and Catalyst outperformed DISCO at reproducing the five target pharmacophores.

Similarity searching in files of three-dimensional chemical structures: analysis of the BIOSTER database using two-dimensional fingerprints and molecular field descriptors

This paper compares the effectiveness of similarity measures based on two-dimensional fingerprints and on molecular fields for identifying pairs of bioisosteric molecules in the BIOSTER database. The results suggest that the two types of descriptor are complementary in nature, each finding some bioisosteric pairs that are not found by the other. This conclusion is confirmed by studies of groups of BIOSTER molecules that share the same activity characteristics, and by experiments that involve combining the two types of similarity measure.

Comparison of conformational analysis techniques to generate pharmacophore hypotheses using catalyst

Generation of reliable pharmacophore models is a key strategy in drug design. The quality of a pharmacophore model is known to depend on several factors, with the quality of the conformer sets used perhaps being one of the most important. The goal of this study was to compare different conformational analysis methods to determine if one was superior to the others for pharmacophore generation using Catalyst/HypoGen. The five methods selected were Catalyst/Fast, Catalyst/Best, Omega, Chem-X and MacroModel. Data sets for which Catalysts models had previously been published were selected using defined quality measures. Hypotheses were generated for each of the data sets and the performance of the different conformational analysis methods was compared using both quantitative (cost and correlation coefficients) and qualitative measures (by comparing the hypotheses in terms of the features present and their spatial relationships). Two main conclusions emerged from the study. First, it was not always possible to replicate the literature results. The reasons for these failures are explored in detail, and a template for use in publications that apply the Catalyst methodology is proposed. Second, the faster rule-based methods for conformational analysis give pharmacophore models that are just as good as, and in some cases better than, the models generated using the slower, more rigorous approaches.